ccnp 2019 program final 2

CCNP 42ND ANNUAL MEETING – JUNE 12 – 15, 2019

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CCNP ANNUAL MEETING 2019

Program

Thomson House (3650 McTavish St.)

McGill University Campus

Montréal, Québec

June 12 - 15

CCNP 42ND ANNUAL MEE

In keeping with CMA guidelines, program content and selection of speakers are the responsibility of the planning committee. Support is directed toward the costs and not to individual speakers through an unrestricted educational grant. The Canadian College of Neuropsychopharmacology appreciates the support of the following sponsors:

GOLD

SILVER LEVEL SPONSORSHIP

BRONZE LEVEL SPONSORSHIP


Acknowledgments

In keeping with CMA guidelines, program content and selection of speakers are the responsibility of the planning committee. Support is directed toward the costs and not to individual speakers through an unrestricted educational grant.

e of Neuropsychopharmacology appreciates the support of the following

GOLD LEVEL SPONSORSHIP

SILVER LEVEL SPONSORSHIP

BRONZE LEVEL SPONSORSHIP

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In keeping with CMA guidelines, program content and selection of speakers are the responsibility of the planning committee. Support is directed toward the costs and not to individual speakers

e of Neuropsychopharmacology appreciates the support of the following


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The Canadian College of Neuropsychopharmacology appreciates the ongoing support of Pfizer Canada Inc. for the Heinz Lehman, Innovations in Neuropsychopharmacology and the Young Investigator Awards.


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CCNP EXECUTIVE & COUNCIL

President Francesco Leri (Guelph) Past President Ridha Joober (Verdun) Vice President Zafiris Daskalakis (Toronto) Treasurer Tak Pan Wong (Verdun) Secretary Darrell Mousseau (Saskatoon) Councillors: Isabelle Boileau (Toronto) Eric Dumont (Kingston) Cecilia Flores (Montréal) Tomas Hajek (Halifax) Alina Marin (Kingston) Naguib Mechawar (Verdun) Abigail Ortiz (Ottawa) Melissa Perreault (Guelph) Junior Member Councillors: Nellie Fotopoulos (Montréal) Anthony Gifuni (Verdun)

LOCAL ORGANIZING COMMITTEE

CCNP 2019 Local Organizing Committee: Cecilia Flores – Douglas Institute/McGill University (Chair) Ridha Joober – Douglas Institute/McGill University Lalit Srivastava – Douglas Institute/McGill University Tak Pan Wong – Douglas Institute/McGill University Naguib Mechawar – Douglas Institute/McGill University Mallar Chakravarty – Douglas Institute/McGill University Paul Clarke – McGill University Marco Leyton – McGill University Mihaela Lordanova – Concordia University Linda Booij – Concordia University Mira Thakur – Douglas Institute


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Presidential Welcome The first meeting of the Canadian College of Neuropsychopharmacology took place in 1978 in Montreal. Since then, prominent Canadian neuroscientists, psychiatrists and their trainees, have been gathering annually to exchange groundbreaking discoveries in basic and clinical research. In 2019, the meeting of the Canadian College of Neuropsychopharmacology is back in Montreal: an internationally renowned center for brain sciences that is also a popular travel destination for its spectacular natural features and rich cultural heritage. This meeting would not have been possible without the outstanding effort of the Local Organizing Committee comprised of Drs. Cecilia Flores (Chair), Ridha Joober, Tak Pan Wong, Marco Leyton, Paul Clarke, Naguib Mechawar, Mihaela Iordanova, Lalit Srivastava, Mallar Chakravarty, Linda Booij and Mira Thakur. As well, on behalf of the Committee, the CCNP Executive and the Council, I wish to thank Ms. Rachelle Anderson for her professional and invaluable assistance. The scientific program showcases a roster of outstanding basic and clinical scientists who will discuss timely and important issues such as sex differences in addiction (Drs. Erin Calipari from Vanderbilt University and Adriana Galvan from UCLA) and cannabis use as risk factor (Drs. Gabriella Gobbi from McGill and Francis Bambico from Memorial University). As well, the 2019 CCNP meeting strongly emphasizes translational approaches by including basic and clinical researchers in the same symposium and by hosting Key Note speakers such Dr. Patricia Conrod and Dr. Yasmin Hurd who are well known for their multilevel approach to mental health research. Finally, as a result of an explicit effort of the Local Organizing Committee to include women, underrepresented minorities and early career scientists/clinicians, the 2019 scientific program well exemplifies the commitment of CCNP to diversity and inclusion. Since the inception of our College, prestigious awards have honored the scientific contributions of scientists and practitioners in neuropsychopharmacology, and 2019 is no exception. This year's winners of the CCNP Awards are: Dr. Guy Rouleau (Heinz Lehmann Award) Dr. Vincenzo De Luca (Young Investigator Award) Dr. Cecilia Flores (Innovations in Neuropsychopharmacology Award) Dr. Lalit Srivastava (CCNP Medal) CCNP also congratulates the winners of the W.G. Dewhurst awards and the trainees selected to present their work in the Next Generation Symposium. This meeting was sponsored by many local and national organizations: Healthy Brains for Healthy Lives (HBHL), Shire (now part of Takeda), Lundbeck, Pfizer, Sunovion, Faculty of Medicine. McGill University, Fonds de Recherche du Québec (FRQ) and Brain Canada Foundation. CCNP would like to thank them all for their important support. I look forward to welcoming you in beautiful Montreal and I hope that you will join us to make the 2019 CCNP annual meeting a memorable event! Sincerely, Francesco Leri, Ph.D. President, CCNP

TABLE OF CONTENTS


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Acknowledgements 2

CCNP Executive & Council 4

Local Organization Committee 4

Welcome Letter 5

Overview of Events 8

Wednesday, June 12, 2019

Heinz Lehmann Award Presentation: Exploring the genetic basis of

neurodevelopmental disorders

Dr. Guy Rouleau 8

Public Talk: How artificial intelligence can contribute to the prevention

of substance use disorders

Dr. Patricia Conrod 8

Abstracts for Oral Presentations 13

Thursday, June 13, 2019

Symposium 1: Gender and addiction

Co-Chairs: Dr. Marco Leyton and Dr. Cecilia Flores 8

CCNP Next Generation Presentation

Chair: Dr. Francesco Leri 9

Symposium 2: Brain adaptations to diet: how fats and sweets mess

with our head

Chairs: Dr. Stephanie Fulton and Dr. Giovanni Hernandez 9


Abstracts for Poster Session I 33

Friday, June 14, 2019

Symposium 3: Unveiling pro-neuroplasticity mechanisms of cannabinoids,

but not in front of the kids!

Chair: Dr. Francis Bambico 10

Presidential Lecture: Cannabis addiction and scientific evidence

Dr. Yasmin Hurd 10


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Symposium 4: Translational neuroimaging in neurodevelopmental

disorders: from animal models to clinical populations and back again

Co-Chairs: Dr. Mallar Chakravarty and Dr. Martin Lepage 10

Symposium 5: The multilingual brain: interactions between several

neurotransmitters during development, reward, and decision-making

Chair: Dr. Giovanni Hernandez 11


Abstracts for Poster Session 2 56

Saturday, June 15, 2019

CCNP Young Investigator Award Lecture: Interaction between current stress

and genome-wide methylation in conferring risk for suicidal ideation

Dr. Vincenzo De Luca 11

Symposium 6: Hippocampal mechanisms underlying depression

vulnerability and treatment

Chair: Dr. Tak Pan Wong 11

CCNP Innovations in Psychopharmacology Award Lecture: Does the

Netrin-1 pathway guide resilience and susceptibility in adolescence?

Dr. Cecilia Flores 12


Author Index for Posters 78


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OVERVIEW OF EVENTS

WEDNESDAY JUNE 12, 2019 12:00 – 19:00 Registration (Ballroom Foyer, 3rd Floor) 13:00 – 17:00 CCNP Council Meeting (Board Room, 4th Floor) 17:00 – 18:00 CCNP Heinz Lehmann Award Presentation (Ballroom 3rd Floor) Dr. Guy Rouleau (McGill University) Exploring the genetic basis of neurodevelopmental disorders 18:00 – 19:00 Public Talk (Ballroom, 3rd Floor) Dr. Patricia Conrod (University of Montreal)

How artificial intelligence can contribute to the prevention of substance use disorders

THURSDAY JUNE 13, 2019 07:30 – 17:00 Registration (Ballroom Foyer) 07:30 – 08:30 Breakfast (Ballroom Foyer) 08:30 – 09:00 Opening Remarks (Ballroom)

Dr. Francesco Leri (CCNP President) and Dr. Cecilia Flores (Chair – Local Organizing Committee)

09:00 – 12:15 Symposium 1: Gender and addiction (Ballroom)

Co-Chairs: Dr. Marco Leyton (McGill University) and Dr. Cecilia Flores (McGill University)

09:00 – 10:00 Dr. Erin Calipari (Vanderbilt University, Tennessee, USA)

A balancing act: females prioritize avoiding aversive stimuli when making value-

based decisions

10:00 – 10:15 Coffee Break (Ballroom Foyer) 10:15 – 11:15 Dr. Adriana Galvan (University of California, California, USA) Cigarette use in the developing adolescent brain 11:15 – 12:15 Dr. Patricia Conrod (University of Montreal)

Gender differences in the effects of substance misuse on structural and functional brain measures in adults and adolescents

12:15 – 13:15 Lunch (Ballroom Foyer) 13:15 – 15:15 CCNP Next Generation Presentation 1 (Ballroom)


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Chair: Dr. Francesco Leri (University of Guelph) 13:15 – 13:35 Aurélie Bussy (McGill University)

The evolution of the hippocampus subfields volume across lifespan in healthy aging 13:35 – 13:55 Nellie H. Fotopoulos (McGill University)

Effects of maternal smoking during pregnancy on brain development in children with ADHD: maternal recall does not tell the whole story

13:55 – 14:15 Duncan G.J. Green (University of Toronto)

Fatty acid amide hydrolase levels in amygdala linked with functional connectivity in fear-related circuitry: a combined positron emission tomography and magnetic resonance imaging study

14:15 – 14:35 Virginia Opara (Concordia University)

Dopamine neurons and transients in the ventral tegmental area reduce prediction error about aversive outcomes

14:35 – 14:55 Maa O. Quartey (University of Saskatchewan)

Aß(1-38) is a negative regulator of Aß(1-42)-mediated neurotoxicity 14:55 – 15:15 Toni C. Spinella (Dalhousie University)

Do human laboratory models of smoking lapse behaviour generalize to non-treatment seeking smokers?

15:15 – 15:30 Coffee Break (Ballroom Foyer) 15:30 – 17:30 Symposium 2: Brain adaptations to diet: how fats and sweets mess with our

head (Ballroom) Co-Chairs: Dr. Stephanie Fulton (University of Montreal) and Dr. Giovanni Hernandez (Douglas Mental Health University Institute)

15:30 – 16:00 Dr. Susanne Le Fleur (University of Amsterdam) Your brain on junk food

16:00 – 16:30 Dr. Stephanie Borgland (University of Calgary) How the orbitofrontal cortex adapts to an obesogenic diet

16:30 – 17:00 Dr. Catharine Winstanley (University of British Columbia) Dietary manipulations alter impulsivity and risky decision making in rats

17:00 – 17:30 Dr. Stephanie Fulton (University of Montreal) Dietary and neural components of obesity-induced motivational deficits

17:30 – 19:30 Posters and Wine & Cheese (Restaurant, Basement Level) FRIDAY JUNE 14, 2019 07:30 – 17:00 Registration (Ballroom Foyer)


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07:30 – 08:30 Breakfast (Ballroom Foyer) 08:30 – 10:30 Symposium 3: Unveiling pro-neuroplasticity mechanisms of cannabinoids,

but not in front of the kids! (Ballroom) Chair: Dr. Francis R. Bambico (Memorial University of Newfoundland: CAMH) 08:30 - 09:00 Dr. Tiziana Rubino (University of Insubria, Italy) Role of the endocannabinoid system inn adolescent brain remodeling 09:00 – 09:30 Dr. Ryan J. McLaughlin (Washington State University, USA) Maternal cannabis vapor exposure dose-dependently impairs behavioral flexibility

in adult offspring 09:30 – 10:00 Dr. Francis R. Bambico (Memorial University of Newfoundland; CAMH) Adolescent exposure to delta-9-tetrahydrocannabinol modifies monoamine

transmission and adaptive emotional responses to aversive stimuli 10:00 – 10:30 Dr. Gabriella Gobbi (McGill University) Bridging preclinical and clinical data in elucidating the age-dependent impact of

cannabis use on mood disorders 10:30 – 10:45 Coffee Break (Ballroom Foyer) 10:45 – 12:00 Presidential Introduction and Lecture (Ballroom) Dr. Yasmin Hurd (Icahn School of Medicine at Mount Sinai, USA) Deciphering the neurobiology of cannabis as “drug” and “medication” 12:00 – 13:00 Lunch and Business Meeting (Ballroom) 13:00 – 15:00 Symposium 4: Translational neuroimaging in neurodevelopmental disorders:

from animal models to clinical populations and back again (Ballroom) Co-Chairs: Dr. Mallar Chakravarty (McGill University) and Dr. Martin Lepage

(McGill University) 13:00 – 13:30 Dr. Mallar Chakravarty (McGill University)

Translational brain imaging in neurodevelopmental disorders using large-scale clinical data and mouse models

13:30 – 14:00 Dr. Synthia Guimond (University of Ottawa)

Subcortical changes in the development of psychosis: a longitudinal study of youth at familial risk for schizophrenia

14:00 – 14:30 Dr. Signe Bray (University of Calgary) Reward and sensorimotor brain systems in Autism spectrum conditions 14:30 – 15:00 Dr. Anthony Vernon (King’s College, UK)

Maternal immune activation and brain development: relevance to psychiatric disorders

15:00 – 15:15 Coffee Break (Ballroom Foyer)


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15:15 – 17:15 Symposium 5: The multilingual brain: interactions between several

neurotransmitters during development, reward, and decision-making (Ballroom)

Chair: Dr. Giovanni Hernandez (Douglas Mental Health University Institute) 15:15 - 15:45 Dr. Willemieke Kouwenhoven (University of Montreal) Investigation of the developmental downregulation and pathological upregulation

of Vglut2 expression in DA neurons 15:45 – 16:15 Dr. Kuei Tseng (University of Illinois at Chicago, USA) Afferent regulation and prefrontal maturation during adolescence 16:15 – 16:45 Dr. Salah El Mestikawy (McGill University; Pierre & Marie Curie University) Regulation of reward and habits by cholinergic interneurons from the striatum 16:45 – 17:15 Dr. Marisela Morales (National Institute on Drug Abuse, National Institutes of

Health, USA) Dorsal raphe combinatorial serotonin-glutamate neurons drive reward by

establishing excitatory synapses on VTA mesoaccumbens 17:15 – 19:15 Posters and Cocktails (Restaurant, Basement Level) 19:30 – 22:30 Banquet and CCNP Awards Presentations McGill Faculty Club and Conference Centre, 3450 McTavish St., Montreal, QC SATURDAY JUNE 15, 2019 07:00 – 12:00 Registration (Ballroom Foyer) 07:00 – 08:30 Breakfast (Ballroom Foyer) 08:30 – 09:30 CCNP Young Investigator Award Presentation (Ballroom) Dr. Vincenzo de Luca (CAMH)

Interaction between current stress and genome-wide methylation in conferring risk

for suicidal ideation

09:30 – 11:30 Symposium 6: Hippocampal mechanisms underlying depression

vulnerability and treatment (Ballroom) Chair: Dr. Tak Pan Wong (McGill University)

09:30 – 10:00 Dr. Jessie Muir (McGill University) Sex specific neural signatures of stress-induced behavioral adapation

10:00 – 10:30 Dr. Tak Pan Wong (Douglas Mental Health University Institute) Hippocampal negative memory engrams enhance stress susceptibility

10:30 – 11:00 Dr. Benjamin Adam Samuels (Rutgers University, USA) Molecular and neural circuit mechanisms underlying antidepressant treatment

resistance


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11:00 – 11:30 Dr. Sonata Suk-Yu Yau (Hong Kong Polytechnic University, Hong Kong) Searching for exercise mimetic to improve stress resilience using animal models

11:30 – 11:45 Coffee Break (Ballroom Foyer) 11:45 – 12:45 CCNP Innovations in Neuropsychopharmacology Award Lecture (Ballroom) Dr. Cecilia Flores (McGill University) Does the Netrin-1 pathway guide resilience and susceptibility in adolescence?

12:45 Closing Remarks Dr. Cecilia Flores (McGill University) 13:00 – 14:00 Lunch (Ballroom Foyer)


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Wednesday, June 12, 2019 Abstracts for Oral Presentations

CCNP Heinz Lehmann Award Lecture Exploring the genetic basis of neurodevelopmental disorders

Dr. Guy Rouleau, MD PhD FRCP(C), The Neuro, McGill University Schizophrenia (SCZ) and autism spectrum disorders (ASD) are common, devastating and poorly treated brain disorders. Twin studies have confirmed that genetic factors significantly contribute to the development of both diseases. In addition, converging evidence suggests that genetically disrupted synaptogenesis and plasticity may, in part, underlie their pathogenesis. We hypothesized that a significant fraction of SCZ and ASD cases result from de novo mutations in genes, particularly those at the synapse. Our strategy was to re-sequence genes encoding synaptic proteins, followed by functional validation of variants in zebrafish, drosophila or mouse hippocampal cell models. Using this method we identified a number of genes that predispose to either or sometimes both of these diseases. Furthermore, we confirmed that there is a higher than expected de novo mutation rate in both SCZ and AUT. Subsequent studies have confirmed and expanded on this hypothesis. De novo mutations may explain part of the missing heritability in SCZ and AUT.

Public Talk How artificial intelligence can contribute to the prevention of substance use disorders Dr. Patricia Conrod, Professeure Titulaire, Dép Psychiatrie, Université de Montréal, Chercheur Boursier Senior, FRSQ; Fondation Julien/Marcelle et Jean Coutu Chair in Social and Community Pediatrics, Centre de Recherche, CHU Ste-Justine, 3175 Côte-Ste-Catherine, Montréal, QC, H3T 1C5, tél: 514 345 4931 (ext 4051) See our new book: New Governance of Addictive Substances and Behaviours https://global.oup.com/academic/product/new-governance-of-addictive-substances-and-behaviours-9780198759836?cc=ca&lang=en& Machine-learning has been identified as a promising approach to identify predictive markers for psychiatric disorders. The use of machine-learning algorithms, which cover complexity/non-linearity in the prediction process along with multimodal assessments, has led to high accuracy in predicting adolescent substance-use. These algorithms not only predict who is at risk and when, but what type of problems are likely to co-occur with substance misuse and new occurrences of cases in novel new contexts. However, predictive psychiatry is not useful and can be harmful if it is not accompanied by evidence-based interventions to reduce risk. Dr. Patricia Conrod will present research on early intervention and prevention strategies that target identified risk factors for early onset substance misuse and mental health concerns. Multiple randomized trials have demonstrated that brief, school-based cognitive behavioural interventions can prevent some risk trajectories from translating into substance use outcomes. Such studies also suggest that managing risk translates to benefits at the population level.

Thursday, June 13, 2019


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Abstracts for Oral Presentations

Symposium 1: Gender and addiction A balancing act: females prioritize avoiding aversive stimuli when making value-based decisions Munir Gunes Kulu, Jennifer E Zachry, Lillian J Brady, Christina Sanders, Patrick Melugin, Amy R Johnson, Alberto J Lopez and Erin S. Calipari Vanderbilt University, Nashville, Tennessee, USA Epidemiological evidence has definitively demonstrated that sex is a critical biological variable in the neuropathology of psychiatric disease, and in many cases women represent a particularly vulnerable population. The stark disparity between the prevalence and prognosis of these disorders in females, and the paucity of data describing the unique neural circuitry underlying these sexual dimorphisms highlight the critical need for preclinical investigation of reward learning and motivation in females. In both humans and animals, females exhibit faster reward learning, increased reward-associated cue responses, and enhanced motivation for drug-associated stimuli. However, in practical contexts, rewards are generally tied to negative consequences and require consideration of the potentially associated aversive outcomes. Our ability to disentangle the specific encoding of these stimuli relies on our ability to dissociate them in behavioral tasks. We have developed a task that dissociates motivated action from cue learning and value processing while highlighting individual response biases. We find that females prioritize the avoidance of negative outcomes over seeking positive, while males have the opposite strategy. These sex-based differences in reward seeking and avoidance offer an ideal model to explore bias and strategy while providing insight into the neurobiological basis of information encoding. By pairing this task with tools to record from and manipulate the cells in the nucleus accumbens - a hub of valence processing - we find that distinct cellular populations in this region [D1 and D2 medium spiny neurons (MSNs)] control sex-specific behavioral strategies. We further outline the complex role of D1 and D2 MSNs in motivated action for valence-specific stimuli. Ultimately, these data show that making conclusions from unidimensional data - behavioral or neural - can lead to broad scale generalizations about sex-specific behaviors that do not accurately reflect the different behavioral strategies and their neural encoding. Cigarette use in the developing adolescent brain Adriana Galván, PhD Department of Psychology, University of California, Los Angeles, Los Angeles, CA 9009, USA Introduction: The onset of smoking frequently occurs during the period of adolescence. Eighty percent of adult smokers become addicted to tobacco by age 18, and people who do not start smoking in adolescence are unlikely ever to do so. However, research on the effects of nicotine on the developing human brain significantly lags behind research on marijuana and alcohol. The goal of this study was to examine how the ontogeny of frontolimbic development circuitry tracks with fluctuations in nicotine use and dependence. Results: Brain function was examined using functional magnetic resonance imaging, in a cohort of adolescent cigarette smokers and adult cigarette smokers. Greater smoking dependence was associated with decreased activation of the prefrontal cortex in smokers versus non-smokers during a self-regulation task. In a risk-taking task, risk level modulated brain activation in the right dorsolateral prefrontal cortex more in smokers than nonsmokers. Using a cue reactivity task, we found that engagement of mesolimbic dopamine circuitry and functional connectivity between the dorsolateral prefrontal cortex and limbic regions in adolescent smokers was associated with smoking craving.


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Conclusions: Given the late development of frontostriatal circuitry, which continues through adolescence, it is possible that smoking may influence the trajectory of brain development during this critical developmental period. They also suggest that adolescent smokers may be more neurobiologically responsive to smoking stimuli than adults. Therefore, targeting adolescents as a means to prevent smoking initiation is crucial to addressing this expensive public health. Gender differences in the effects of substance misuse on structural and functional brain measures in adults and adolescents Patricia J. Conrod, Xavier Navarri, Sima Noorbakhsh, Mohammed H. Afzali University of Montreal, Montreal, QC Objective: Men and women are differentially at risk for substance use disorders (SUDs), and it is not clear if sex and gender differences in the neurocognitive consequences of substance use disorders mediate such risk. Using two large studies, one meta-pooling analysis of alcohol and cannabis dependence case-control neuroimaging studies and a second developmentally sensitive longitudinal design, the authors investigated age-related effects of cannabis and alcohol on neurocognitive measures in male and females. Method: Meta-analysis of the ENIGMA-Addiction alcohol and cannabis studies compared the size of case-control differences in men and women. A second population-based sample of 3,826 seventh grade students from 31 schools consisting of 5% of all students entering high school in 2012 and 2013 in the Greater Montreal region were assessed annually for 4 years on alcohol and cannabis use, recall memory, perceptual reasoning, inhibition, and working memory, using school-based computerized assessments. Multilevel regression models were used to simultaneously test the interaction of gender with vulnerability, concurrent and lagged within-subject effects on each cognitive domain. Results: Gender differences were revealed in both analyses, suggesting that males might be more sensitive to the effects of cannabis on brain development, while females might be more sensitive to the effects of alcohol, particularly in adulthood. Conclusions: While gender differences in substance use behaviours are highly tolerated and normalized in society, closer examination of the effects of substance misuse on brain measures suggests gender-specific effects of SUDs on brain health. CCNP Next Generation Presentations The evolution of the hippocampus subfields volume across lifespan in healthy aging Aurélie Bussy1,2, Eric Plitman2,3, Alyssa Salaciak2, Sarah Farzin2, Saashi A. Bedford1,2, Stephanie Tullo1,2, Marie-Lise Beland2, Gabriel A. Devenyi2,3, M. Mallar Chakravarty1,2,3,4 1Integrated Program in Neuroscience, McGill University, Montreal, Canada 2Computational Brain Anatomy Laboratory, Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Canada 3Department of Psychiatry, McGill University, Montreal, Canada 4Department of Biomedical engineering, McGill University, Montreal, Canada Introduction: The hippocampus plays an important role in memory consolidation and spatial memory. Healthy aging (HA) is associated with a gradual decline in memory and shrinkage of hippocampal volume. The hippocampus is also one of the major areas wherein Alzheimer’s Disease (AD) pathologies are identified. Importantly, the progressive degeneration of the hippocampus and its subfields across the adult lifespan is presently not well characterized. The goal of the present work is to evaluate and identify volumetric modifications in hippocampal subfields during HA. Methods: The present work included 180 healthy participants (ages 18-80) to investigate lifespan


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changes in hippocampus volume during HA. The volume of the hippocampus and its subfields (Cornus Ammonis (CA)1, CA2CA3, CA4 and dentate gyrus (CA4DG), stratum radiatum/lacunosum/moleculare, subiculum, fimbria, fornix, alveus and mammillary bodies) were estimated using T1-weighted images (1mm3 voxels) and the MAGeT Brain algorithm. Analyses were carried out using general linear models. Akaike information criterion was used to compare models and select the most probable age relationships from multiple fits (e.g. linear, quadratic, and cubic) for each structure of interest. A Bonferroni correction have been used for multiple comparisons correction, at a p<0,05 threshold for significance. Analyses included sex, MMSE score, years of education, and APOE4 status as covariates. Results: Total hippocampus showed an interaction between cubic age and sex. Including total hippocampal volume as a covariate, the right CA1 and right alveus were positively cubically related to age (p=0.008 and p<0.001, respectively), and the right and left CA4DG were negatively linearly related to age (p=0.04 and p=0.001, respectively). Conclusion: Specific subfields of the hippocampus are more (e.g. CA1, alveus) or less (e.g. CA4DG) preserved in HA. Future aims for this study include extending analyses to additionally include patients with mild cognitive impairment and AD. Effects of maternal smoking during pregnancy on brain development in children with ADHD: maternal recall does not tell the whole story Nellie H. Fotopoulos, Sarojini M. Sengupta, Boris Chaumette, Gabriel A. Devenyi, Sherif Karama, M. Mallar Chakravarty, Aurelie Labbe, Natalie Grizenko, Norbert Schmitz, and Ridha Joober Background: Maternal smoking during pregnancy (MSDP) is considered a risk factor for ADHD. While the mechanisms underlying this association are not well understood, MSDP may impact the developing brain in ways that lead to ADHD. Here, we investigated the effect of prenatal smoking exposure on cortical brain structures in children with ADHD using two methods of assessing prenatal exposure: maternal recall and epigenetic typing. Methods: Exposure groups were defined according to: (1) maternal recall (+MSDP: n = 24; -MSDP: n = 85) and (2) epigenetic markers (+EM: n = 14 -EM: n = 21). CIVET-1.1.12 and RMINC were used to acquire cortical brain measurements and perform statistical analyses, respectively. The vertex with highest significance was tested for association with the Continuous Performance Test (CPT) dimensions. Results: Approximately 30% of children considered -MSDP were +EM. + EM children (n = 10), had significantly smaller surface area in the right orbitofrontal cortex (ROFc), middle temporal cortex (RTc) and parahippocampal gyrus (RPHg) (15% FDR) compared to -EM children (n = 20). Cortical surface area in the RPHg significantly correlated with CPT commissions-error T-scores (df = 27; p = .006). No differences of brain structures were identified between +MSDP and –MSDP. Conclusions: This study suggests that molecular markers may be useful to better define exposure to environmental risks, as compared to fallible human recall. This approach may help to reconcile many discrepancies in the literature investigating the risk associated with early exposure to cigarette smoking. Fatty acid amide hydrolase levels in amygdala linked with functional connectivity in fear-related circuitry: a combined positron emission tomography and magnetic resonance imaging study Duncan G.J. Green, HBSc1,2,9, Stephen J. Kish, Ph.D., 2-7, Rachel F. Tyndale, Ph.D. 4,6-8,9 , Matthew N Hill, Ph.D.10 Antonio P. Strafella, MD, Ph.D.4,5,9, Junchao Tong, Ph.D.,2- Tina McCluskey MSc, Duncan J Westwood, BSc1 Sylvain Houle, MD, PhD4,5,9, Nancy J. Lobaugh, Ph.D.5,9, Isabelle Boileau, Ph.D.1,2,4-6,9, Jinhee Kim, Ph.D5. 1Addiction Imaging Research Group, 2Human Brain Lab, 3Translational Addiction Research Laboratory, 4Campbell Family


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Mental Health Research Institute and 5Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada; 6Departments of Psychiatry, 7Pharmacology & Toxicology, 8Family and Community Medicine and 9Institute of Medical Sciences, University of Toronto, Toronto, Canada, 10Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy & Psychiatry, University of Calgary, Calgary, Canada Background: Human imaging studies have implicated abnormal fronto-amygdala activity in the pathogenesis of Post-Traumatic Stress (PTSD) and anxiety disorders. A recent magnetic resonance imaging (MRI) study finds that functional connectivity (FC) within this ‘fear-related’ circuit is linked with a common genetic polymorphism for fatty acid amide hydrolase (FAAH 385A (rs324420)), the catabolic enzyme for the endogenous cannabinoid anandamide (Dincheva et al., 2015). The goal of the current study was to directly test the hypothesis that FAAH levels in the amygdala, measured with in vivo positron emission tomography (PET) imaging, are correlated with functional coupling (FC) between amygdala and ventromedial prefrontal cortex (vmPFC). Methods: 31 healthy subjects (19 female; ages 19-58), genotyped for the FAAH polymorphism (385A (rs324420)) completed PET imaging with the FAAH probe [C-11]CURB as well as resting-state functional MRI scans. The FC r-map for bilateral amygdala was obtained using a seed-to-voxel correlation approach. A whole-brain regression analysis with amygdala [C-11]CURB binding mean value as a covariate was conducted on equally-weighted bilateral amygdala FC z-maps (FDR corrected cluster-level p < 0.05) to identify brain regions whose FC with the amygdala correlated with amygdala [C-11]CURB. Results: We found a negative correlation between mean amygdala[C-11]CURB binding and FC between the amygdala and vmPFC (R2=0.77). However, carriers of the C385A variant (n = 11) did not differ significantly in FC (z=-0.0194(A/A; A/C) vs -0.0329(C/C); p =0.6). Conclusions: Our results extend Dincheva et al. (2015)’s finding that individuals with lower FAAH levels (C385A) have enhanced amygdala-vmPFC coupling by showing a link between in vivo measurement of FAAH levels in amygdala and FC in a brain circuit that regulates fear response. This result supports the view that FAAH inhibitors could modulate neural processing in fronto-amygdala fear-regulation circuitry known to be dysregulated in disorders such as PTSD. Dopamine neurons and transients in the ventral tegmental area reduce prediction error about aversive outcomes Virginia Opara & Ashraf Mahmud, M.Sc., Marie-Pierre Cossette, PhD, Belinda P.P. Lay, PhD, Mihaela D. Iordanova, PhD Department of Psychology, Center for Studies in Behavioural Neurobiology/Groupe de Recherche en Neurobiologie Comportementale, Concordia University, Montreal, Quebec, Canada Learning depends on prediction error, which is the mismatch between real and expected outcomes. Blocking best illustrates the role of prediction error in learning. Learning about the association between a novel cue and an outcome is impaired in the presence of a good predictor for that outcome. This occurs because in the presence of the good predictor the outcome is expected and therefore the prediction erroris minimal. Dopamine (DA) neuronal firing in the Ventral Tegmental Area (VTA) mimics prediction error in reward. Here, we sought to determine whether VTA DA has any role in aversive prediction error. To address this, we employed an aversive blocking paradigm along with bidirectional optogenetic manipulations of VTA DA neurons. Optogenetically activating dopamine neurons in the VTA at the time of an expected shock in a blocking design attenuated learning about the novel cue and shock. Conversely, optogenetically inhibiting VTA dopamine neurons at the same time point led to unblocking, that is learning about the association between the novel cue and the outcome. These results were taken as evidence for the role of VTA DA in aversive prediction-error such that activation and inhibition of VTA DA neurons reduces and increases, respectively, aversive prediction error. Additionally,


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we showed that this aversive prediction error signal is regulated by the VTA-nucleus accumbens (NAC) pathway. Stimulation of VTA DA terminals in the NAC at time of the expected shock in blocking augmented the blocking effect, much like VTA DA cell body stimulation. Our findings reveal that the VTA DA neurons and their targets (NAC) regulate aversive prediction-error. When considered collectively with similar research in the field of reward, our research points to a valence-specific mechanism Aß(1-38) is a negative regulator of Aß(1-42)-mediated neurotoxicity Maa O. Quartey, PhD, Jennifer N.K. Nyarko, PhD, Kaeli J. Knudsen, MSc, Paul R. Pennington, Maria Alejandra Castilla Bolanos, MSc, Josef Buttigieg, PhD, Jocelyn R. Barnes, MSc, Matthew P. Parsons, PhD, Carlos De Carvalho, PhD, and Darrell D. Mousseau, PhD Introduction: The beta-amyloid (Aß) peptides cleaved from the Amyloid Protein Precursor (APP) are thought to exacerbate the progression of neuropathology associated with Alzheimer disease (AD). However, recent work has shown that structural and aggregation properties of Aß peptides with carboxyl terminus truncations differ significantly (1). We previously reported that the shorter, less hydrophobic Aß(1-38) peptide, displays characteristics similar to those of the AD-related and more hydrophobic Aß(1-42). However, co-incubation with Aß(1-38) can disrupt the ß-sheet-rich, oligomerizing potential of Aß(1-42). We used several functional assays to compare the profiles of these two (patho)physiologically relevant Aß peptides in isolation and in equimolar mixtures. Methods: All peptides were reconstituted and stored in HFIP to disrupt any pre-existing hydrophobic ß-sheet structures. We studied cell survival in rat hippocampal cell cultures treated with either Aß(1-38), Aß(1-42), or both peptides. Whole-cell patch clamp electrophysiology and long-term potentiation paradigms based on hippocampal preparations were used to study the Aß peptide effects on membrane conductance and synaptic plasticity, respectively. We also generated a bigenic Aß(1-38)/Aß(1-42) strain of Caenorhabditis elegans to monitor the effect of the expression of these two peptides alone or in combination in an in vivo system. Results: In isolation, Aß(1-38) displays characteristics similar to –albeit less pronounced than– those of Aß(1-42). However, co-incubation with Aß(1-38) can disrupt the ß-sheet-rich, oligomerizing potential of Aß(1-42) and mitigate the detrimental effects of Aß(1-42) in hippocampal cell cultures and in C. elegans. Aß(1-38) also reverses the negative impact of Aß(1-42) on membrane conductance and on long-term potentiation. Distinct sex differences in levels of soluble Aß(1-38) relative to soluble and insoluble (plaque/aggregated) Aß(1-42) levels are observed in autopsied AD brain extracts. Conclusions: Aß(1-38) appears to be a natural, negative regulator of Aß(1-42) function. This knowledge could alter our understanding of AD progression and inform on designing appropriate intervention strategies. Do human laboratory models of smoking lapse behaviour generalize to non-treatment seeking smokers? Toni C. Spinella, BA, MSc Candidate, Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada. Hera E. Schlagintweit, PhD, Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada. Sean P. Barrett, PhD, Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada Introduction: Human laboratory-based smoking lapse paradigms have been shown to be sensitive to nicotine deprivation and medication effects among heavy, treatment seeking smokers; however, their generalizability to other subgroups of smokers remains unknown. We aimed to examine the extent to which a laboratory-based smoking lapse task was sensitive to pharmacological manipulations in a non-treatment seeking cohort of smokers.


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Methods: Thirty-six (13 female) healthy, non-treatment seeking smokers were community-recruited from the Halifax Regional Municipality to investigate the extent to which different nicotine or tobacco containing products impact a smoker’s ability to delay their smoking behaviour. Following a 12-hour period of nicotine deprivation, participants received nicotine inhalers (NI), placebo inhalers (PI), nicotine-containing tobacco (NT), and denicotinized tobacco (DT) across four sessions in double-blind, randomized order. They subjectively rated each product and we examined their ability to delay smoking utilizing a monetized smoking lapse paradigm and then measured their subsequent cigarette self-administration using a progressive-ratio task (PRT). Results: Participants rated products significantly different on measures of nicotine and tar content, liking, and strength (all p < 0.001). However, none of the products were found to reliably delay the onset of subsequent smoking (F = 1.946, p = 0.147). In contrast, the pre-administration of NT was found to reduce overall number of self-administered cigarette puffs administered relative to PI (t = 2.775, p = 0.014, 95% CI [0.444, 5.106]). Conclusion: Although participants were able to reliably distinguish between products that differed in their nicotine/tobacco contents, none of products dependably impacted participant’s ability to resist subsequent smoking. Thus, in a heterogeneous sample of non-treatment motivated smokers, pharmacological manipulations appear to be ineffective in delaying subsequent smoking behaviour. Such findings elude to the importance of non-pharmacological factors, like motivation, in facilitating decisions to smoke. Symposium 2: Brain adaptations to diet: how fats and sweets mess with our head Your brain on junk food Susanne E La Fleur, University of Amsterdam, Amsterdam, The Netherlands Added sugar, often consumed in the form of sweetened beverages, is currently labeled as a big evil that increases our risk to develop obesity, cardiovascular diseases, and diabetes. Only a few decades ago, however, saturated fat received a similar negative label. Instead of singling out one of these factors we are interested to understand how fat and sugar intake interact, thus influencing brain function, metabolism and behavior. We recently showed that free choice during simultaneous fat and sugar consumption exponentially increases the risk of overeating, obesity development and occurrence of metabolic disturbances in rats. Moreover, the brain’s response to this obesogenic choice diet does not promote counter regulatory mechanisms but reflects high energy demands (i.e. the brain shows a fasting-like response) pointing to aberrant nutrient signaling. During this presentation, the effects of the choice diet on the reward system will be reviewed which includes changes in neuropeptide signaling in striatum and neuronal responses to sugar drinking while eating a fatty diet or a healthier grain-based chow diet. How the orbitofrontal cortex adapts to an obesogenic diet

Stephanie L. Borgland, Benjamin K. Lau, Ciaran Murphy-Royal, Manpreet Kaur, Jaideep S. Bains, Grand R. Gordon University of Calgary, Calgary, AB Background: The orbitofrontal cortex (OFC) plays a key role in the cognitive and emotional processing of decision-making. It is well established that the endogenous cannabinoid (endocannabinoid) system in the brain is important for appetite regulation. However, it is unknown if endocannabinoid signalling in the OFC is altered by an obesogenic diet. We tested the hypothesis that an obesogenic diet can modulate endocannabinoid mediated synaptic transmission in the OFC.


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Methods: Male Long Evans rats were given restricted (1h /day), extended (24h/day) or no (chow only) access to a cafeteria diet for 40 days. We used in-vitro patch clamp electrophysiology in lateral OFC slices to record GABAergic inhibitory postsynaptic potentials (IPSCs) onto pyramidal neurons within layer II/III. Results: GABAergic synaptic transmission onto OFC pyramidal neurons was reduced following extended, but not restricted access to a cafeteria diet. This suppression of inhibition was partly reversed by the CB1 receptor antagonist, NESS-0327, indicating the presence of tonic levels of endocannnabinoids. Associated with elevated endocannabinoid tone was an impairment of inhibitory long-term depression (iLTD). We further showed that these obesity-induced synaptic alterations were mediated by upstream activation of Group 1 metabotropic glutamate receptors (mGluRs). Specifically, endocannabinoid tone was blocked in the presence of the mGluR5 antagonist, MTEP, while mGluR-iLTD induced by the Group 1 mGluR agonist, DHPG was impaired in obese animals. Interestingly, the impairment in iLTD was rescued in obese animals by restoring glutamate homeostasis, via the cystine/glutamate exchanger and glutamate transporter-1 in astrocytes. Conclusions: Together, our findings suggest that long-term exposure to a palatable diet alters astrocyte modulation of glutamate homeostasis within the OFC, resulting in enhanced endocannabinoid signalling and tone via Group 1 mGluR activation, which then leads to decreased GABAergic synaptic transmission. Obesogenic diets disrupt synaptic transmission in the OFC which may influence cognitive and emotional processing of decision-making in obesity. Dietary manipulations alter impulsivity and risky decision making in rats Catharine Winstanley, University of British Columbia, Vancouver, BC Introduction: As obesity rates continue to skyrocket, understanding the complex interplay between diet, weight, and cognition remains a key research priority. Methods: We first investigated the effects of calorie-equivalent high-fat or high-sugar diet in male Long Evans rats learning to perform the 5-Choice Serial Reaction Time task (5CSRT). We also assessed 5CSRT performance in leptin knockout rats vs wildtype littermates, when fed standard rat chow or a high fat diet. More recently, we have evaluated the effects of unrestricted access to a junk food diet on decision making on the rat gambling task (rGT). Results: Rats on the high-fat diet showed a selective and sustained enhancement of impulsive responding on the 5CSRT, with no change in other behavioural measures, even though they were not obese. In contrast, the high-sugar diet had no effect on task performance. Critically, animals fed the high-fat diet exhibited reduced D2 receptor protein in the ventral striatum, a biological finding repeatedly associated with a pro-addiction phenotype. In contrast, leptin knockout rats did not show impulse control deficits at baseline, and striatal dopamine receptor expression was unchanged as compared to wild type rats, although leptin-deficient animals were hyper-impulsive in response to amphetamine. Finally, free consumption of a junk food diet increase risky decision making in animals that had previously been making optimal choices on the rGT. Conclusions: While chronic exposure to even limited amounts of an unbalanced, high-fat diet may weaken impulse control, obese animals are not necessarily more impulsive, although obesity may weaken impulse control in states of increased catecholaminergic tone, such as stress. Junk food diet also selectively impaired decision making in animals previously capable of advantageous choices. Collectively, these data indicate that high calorie diets can enhance the expression of impulsivity and risk-preference, traits that are associated with addiction and impulse control disorders. Dietary and neural components of obesity-induced motivational deficits Stephanie Fulton, University of Montreal, Montreal, QC


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Lipids play a fundamental role in the CNS as structural components of neural cells, sources of cellular energy and as signaling molecules. Findings will be presented showing that lipids, both diet-derived and exogenous, can modulate brain reward circuitry and modulate motivated behaviors. First, the impact of high lipid diets on metabolic dysfunction, neuroimmunity, motivation and mood will be discussed. results will be presented describing the striatal output pathways underlying the impact of lipid overload on anhedonia and anxiety-like behavior. Second, results showing the, direct effects of fatty acids on mesolimbic dopamine function will be discussed. Multiple levels of analysis show that dopamine neurons are capable of taking up fatty acids and that they can be esterfied into lipid droplets. Blockers of fatty acid intracellular transport diminish the effects of midbrain fatty acids on food-seeking and neuronal activity. Finally, recent data will be presented on the behavioral, neurolipid and neuroprotective actions of polyunsaturated fatty acids and GPR120, a g-protein coupled receptor activated by omega-3 fatty acids. Research supported by the CIHR and NSERC.


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Friday, June 14, 2019 Abstracts for Oral Presentations

Symposium 3: Unveiling pro-neuroplasticity mechanisms of cannabinoids, but not in front of the kids! Role of the endocannabinoid system in adolescent brain remodeling Pamela Prini, Cristina Manenti and Tiziana Rubino Department of Biotechnology and Life Sciences, University of Insubria, Busto Arszio (VA), Italy Introduction: Epidemiological data provide evidence that adolescent exposure to Cannabis is an important contributing factor to psychiatric vulnerability. Data collected so far in animal models suggest that adolescent, but not adult, exposure to THC negatively affects developmental changes typical of the adolescent brain, thus leading to altered adult brain functionality and behavior. Indeed, the adolescent brain undergoes intensive processes of neuronal refinement characterized by synaptic pruning and increased myelination. In the brain, the endocannabinoid system (ECS), the main target of Cannabis, is an important lipid signaling system involved in the modulation of synaptic plasticity and perinatal neurodevelopment. However, its role in events relevant for the adolescent brain remodeling still needs to be clarified. On these bases, the aim of the present work is to investigate if and how the ECS acts on synaptic refinement and white matter development that characterize adolescent brain maturation. Methods: To dissect precisely the dynamic of the involvement of the ECS in neuronal refinement and myelination processes occurring in the prefrontal cortex of adolescent female rats, we modulated the endocannabinoid tone through the administration of specific drugs acting on the ECS components during the PND 28-32, 33-37 and 38-42. At the end of treatment, we evaluated markers of synaptic plasticity and myelination. Results: Among all the processes studied, the most consistent evidence support a role for CB1 receptor stimulation in promoting myelination processes. Moreover, data, although preliminary, seem to suggest that CB1 receptor blockade prevent the pruning event. Conclusion: We propose that THC disruption of the role played by the endocannabinoid system in the adolescent brain maturation may be part of the molecular underpinnings that make the adolescent brain vulnerable to THC long-lasting adverse effects. Maternal cannabis vapor exposure dose-dependently impairs behavioral flexibility in adult offspring Timothy G. Freels, Ph.D., Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA Collin R. Warrick, B.Sc., Department of Pharmacology, Johns Hopkins University, New York, NY, USA Janelle M. Lugo, B.Sc., Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA Ryan J. McLaughlin, Ph.D., Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA Introduction: Cannabis is the most commonly used illicit substance among pregnant women, yet effects of prenatal cannabis exposure on cognitive functioning remain largely unknown. With recreational cannabis laws now in effect in 11 states and counting, there is growing concern that cannabis use during pregnancy could increase dramatically in the coming years. Thus, there is an urgent need to better understand the impact of prenatal cannabis exposure on cognitive functioning later in life. Methods: We investigated whether exposure to vaporized cannabis during pregnancy alters cognitive flexibility in male and female offspring using an attentional set-shifting task. Female dams were passively exposed to vaporized cannabis extract (29.2% THC; 50 or 400mg/mL; 1 puff


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every 2 min for 1 hr, twice daily) or vehicle vapor throughout mating and gestation. Separate cohorts of dams were not exposed to any vapor during pregnancy. Beginning at postnatal day 55, all offspring were trained to press a lever that was paired with delivery of a cue light to receive a sugar pellet reward. On the day after learning criteria were reached, rats were tested in the set-shifting task, whereby they had to disregard the previously learned strategy in favor of an egocentric spatial strategy. On the final day of testing, rats were tested in a reversal-learning task that required them to press the lever opposite of the previous task. Results: Rats prenatally exposed to high (400 mg/ml) but not low (50 mg/ml) concentrations of vaporized cannabis extract resulted in significant impairment in attentional set shifting compared to no vapor control rats. Specifically, high-dose prenatal cannabis exposure led to an increased number of never-reinforced and regressive errors, which is indicative of deficits in acquiring and maintaining the new rule. Conclusions: These data indicate that maternal cannabis vapor exposure dose-dependently impairs behavioral flexibility when tested in adulthood. Adolescent exposure to delta-9-tetrahydrocannabinol modifies monoamine transmission and adaptive emotional responses to aversive stimuli Francis R. Bambico, PhD Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador; Centre for Addiction and Mental Health, Toronto, Canada Introduction: Cannabinoid exposure during adolescence has been shown to engender persistent emotional and amotivational disturbances that may be mediated by altered monoamine activity. Methods: We employed a rodent model of stress controllability and chronic cannabinoid consumption combined with electrophysiology to examine cannabinoids effects on emotional reactivity and stress adaptation. Results: Chronic exposure to delta-9-tetrahydrocannabinol (delta-9-THC) during adulthood or adolescence did not lead to profound anxiety-like nor passivity-like coping. However, adolescent exposure resulted in a significant decrease in the latency to switch between active and passive coping, to an anhedonia-like reduction in sucrose preference, as well as a potentiation of consummatory successive negative contrast. These behavioural abnormalities were paralleled by significant reductions in dorsal raphe serotonergic neural activity without changing locus coeruleus noradrenergic neural activity, confirming earlier reports that chronic cannabinoid exposure during critical developmental periods could result in increased vulnerability of the monoaminergic system, and in depressive-like abnormalities in the emotional processing of aversive stimuli. In an attempt to further probe into potential neurobehavioural correlates of cannabinoid-induced vulnerabilities, we have been investigating the neuroplastic effects of stress exposure on age-dependent adaptations of downstream prefrontocortical pathways. We found that prefrontocortical activation is modulated by endocannabinoid transmission and differentially linked to stress controllability and predictability. Conclusion: Adolescent delta-9-THC exposure can lead to persistent behavioural deficits, likely linked to interferences in the developmental trajectories of behavioural systems involved in cognitive-affective regulation. Bridging preclinical and clinical data in elucidating the age-dependent impact of cannabis use on mood disorders Gabriella Gobbi, MD, PhD, McGill University, Montreal, QC


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Introduction: Besides the use of cannabis as a medicine in 1999, Canada in October 2018 has legalized the recreational use of Cannabis with a prohibition to use cannabis for people under age 18. Canadian youths have among the highest rates of cannabis use compared to their peers in other industrialized countries (UNICEF Office of Research, 2013), and legalization seems to do not decrease this tendency. Many studies have been published concerning the effects of cannabis on the development of psychosis, poor academic performance, and lowered driving safety, especially in youth, when the brain is still under development. However, limited studies have focused on mood disorders and suicidality. Methods: Preclinical studies including in vivo electrophysiology and behavioral pharmacology were used to measure the impact of adolescent cannabis on mood in young adulthood. Meta-analysis methodology and systematic review were used to evaluate the impact in humans. Results: Electrophysiological experiments have shown that cannabis interacts directly with the serotoninergic system, the main neurotransmitter system regulating mood and emotions. While in a short-term period cannabis enhances serotonin activity producing a euphoric-like state, in long-term induces a decrease of serotoninergic system. Moreover, long-term cannabis consumption enhances the noradrenergic system electrical activity, a neurotransmitter involved in the regulation of anxiety (Bambico et al., Neurob. Dis. 2010) Finally, data from large epidemiological studies as well as a recent meta-analysis carried out in Dr Gobbi's laboratory have pointed out the evidence that cannabis when smoked during adolescence increases the risk for depression in young adulthood even in the absence of a pre-morbid condition (Gobbi et al, JAMA Psychiatry 2019). Likewise, an increased risk for suicidal ideations and suicidal attempts were also associated with adolescence cannabis consumption. Conclusion: Long-term cannabis consumption in adolescence could affect the emotional brain by increasing the risk for depression and suicidal behavior. Presidential Introduction and Lecture Deciphering the Neurobiology of Cannabis as “Drug” and “Medication” Yasmin L. Hurd, Icahn School of Medicine at Mount Sinai, New York City, New York, USA Introduction: There has had a dramatic shift in the sociopolitical landscape in the legalization of cannabis for both medical and recreational purposes. Much attention has been placed on the medicinal promise that cannabis might possess, but the spotlight has also raised awareness about the relative lack of scientific studies that are necessary to provide critical neurobiological insights about the potential long-term mental health impact and medicinal qualities of this complex plant. The goal of this project is to determine the neurobiological consequences of specific cannabinoids relevant to neuropsychiatric risk and therapeutic properties. Methods: Preclinical rodent models, postmortem human brain specimens and human clinical populations are investigated in relation to the effects of developmental cannabis/THC exposure and in association with cannabidiol (CBD) administration relevant to opioid addiction and related phenotypes. Translational and multidisciplinary approaches consist of molecular, biochemical, epigenetic and behavioral studies. Results: Distinct and sometimes contrasting effects are apparent for THC and CBD on various addiction-related behaviors as well as on specific neural systems linked to synaptic plasticity. Conclusions: There are critical risk/benefit aspects of specific cannabinoids in regard to the long-term impact on discrete neurobiological systems and phenotypes relevant to psychiatric and addiction disorders that emphasize the need for significant research efforts to decipher the complex cannabis plant.


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Symposium 4: Translational neuroimaging in neurodevelopmental disorders: from animal models to clinical populations and back again Translational brain imaging in neurodevelopmental disorders using large-scale clinical data and mouse models Mallar Chakravarty, McGill University, Montreal, QC Different neurodevelopmental disorders often share common risk factors, yet have complex and varied clinical manifestations, even within diagnostic categories. In his talk, Dr. Chakravarty will present work on how we can use large neuroimaging datasets to examine factors that influence heterogeneity (genetics, age, sex, etc) within specific neuropsychiatric disorders. He will then demonstrate how we can use experimental models to further study environmental risk factors and their influence on neuroanatomical, behavioural, and cognitive trajectories. The goal is to demonstrate how these two streams of inquiry can be used to provide complementary information regarding how similar loads of genetic and environmental risk may give rise to the significant variability consistently observed in individuals suffering from neurodevelopmental disorders. Subcortical changes in the development of psychosis: a longitudinal study of youth at familial risk for schizophrenia Synthia Guimond, Suraj Sarvode, Carolina Makowski, Mallar Chakravarty, Matcheri Keshavan University of Ottawa, Ottawa, ON Objective: Relatives of individuals with schizophrenia have a higher incidence of developing the illness compared to the general population. Studying youth at familial high-risk (FHR) of developing schizophrenia offers a unique opportunity to identify markers of transition to psychosis. Previous studies have identified abnormal shape and volume of the amygdala and hippocampus in FHR, but it remains unclear if these phenotypic aberrations are predictive of further transition to psychosis. Method: To determine whether FHR individuals who develop psychosis have abnormal neurodevelopmental trajectories of the amygdala and hippocampus, we investigated longitudinal changes of these structures in 82 FHR individuals and 56 healthy controls, during a 4-year period. Ten individuals from the FHR group transitioned to psychosis. Volumes and local displacement of the amygdala and hippocampus were obtained using the MAGeT Brain pipeline, and age-centered longitudinal changes in each group were compared using a linear mixed-effects model in Surfstat. Results: FHR individuals who converted to psychosis showed a significant increase in concavity in the right dorsal amygdala with age, compared to other FHR individuals and healthy controls (p < .05 FDR corrected). No age by group interaction was observed on hippocampal shape, but FHR individuals who did not convert to psychosis had marginally significant smaller left subiculum compared to healthy controls (p < .07). Conclusion: Our results suggest that abnormal shape trajectories in the right dorsal amygdala in FHR youth could be a potential marker of transition to psychosis. Abnormalities in the amygdala have been previously observed in neuroleptic naïve patients with schizophrenia, and alterations in this region could be related to aberrant emotion processing in premorbid phase of the illness. Future studies should investigate if targeted treatments in FHR individuals can impact such changes in amygdala, and potentially even postpone or prevent the transition to psychosis. Reward and sensorimotor brain systems in Autism spectrum conditions Signe L Bray, University of Calgary, Calgary, AB


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Introduction: Many theories have been proposed to explain the symptoms of Autism Spectrum Conditions (ASCs). These theories make both unique and overlapping neurophysiological predictions. For example, symptoms of ASCs have been theorized to stem from atypical social cognition, social motivation or sensory processing, with implications for the associated brain systems. But, identifying the structural and functional brain correlates of ASCs has been a challenge, not the least due to wide heterogeneity in this population. Paradigms that can be tested in both human and animal models may enable more rapid progress and deeper understanding of mechanisms. Methods: We have used neuroimaging with magnetic resonance imaging (MRI) and electroencephalography (EEG) to investigate neuro-anatomical and -functional differences in children and youth with ASCs in two domains that readily lend themselves to parallel investigations in animal models. First, we have investigated anatomy and responses of the brain’s reward system. Second, we are looking at somatosensory processing and cortical responses to tactile stimulation. Results: Our work to date has suggested that there are subtle neuroanatomical alterations in ASC, relative to typically developing (TD) controls in subcortical brain regions. However, we have not found evidence for atypical behavior or functional responses. I will describe our approach to studying tactile sensory responses in ongoing work. Conclusion: ASCs are heterogeneous conditions with likely diverse underlying causes. Paradigms that can readily be adapted to both human and animal models are needed to advance insight about symptom mechanisms and to understand avenues for mitigating negative symptoms. Maternal immune activation and brain development: relevance to psychiatric disorders Anthony C. Vernon, PhD, FHEA, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, SE5 9RT, United Kingdom Introduction: Maternal immune activation (MIA) is associated with elevated risk for multiple psychiatric disorders in the affected offspring. We lack however, a detailed understanding of the impact of MIA on critical juvenile periods of brain development at the systems level, using translational cross-species measures, such as magnetic resonance imaging (MRI). Methods: Utilising a validated rodent MIA model, in which the pregnant dam is exposed to the viral mimetic poly (I:C) (4 mg/kg i.v.) at gestational day 15 or saline as a control, we investigated the imapct of MIA using ex vivo cross-sectional structural MRI, diffusion MRI and quantative relaxometry and longitudinal in vivo structural MRI and prefrontal cortex 1H-MR spectroscopy (MRS) in the affected offpsrping from post-natal day (P)21 to 6 months of age. MRI data were analysed using operator-independent voxel-wise methods, corrected for multiple comparions using the false discovery rate (5%). 1H-MRS data were analysed using LC model and compared across groups using linear mixed effect models with age, mIA and treatment as factors, respectively, with alpha=0.05. Results: Exposure to MIA results in time- and sex-dependent abnormalities in brain structure and metabolism. These include decreased prefrontal cortex levels of glutathione (p<0.05; d=1.08), taurine (p<0.01; d=1.35) and N-acetyl-aspartate (p<0.05; d=1.05) at P180, acommpanied by widespread, dynamic brain volume changes (5% FDR corrected). Conclusions: Prenatal exposure to MIA results into early entry into an atrypical neurodevelopmental trajectory. We are now exploring the links behavioural dysfunction and establishing the cellular and molecular correlates of our MRI findings. Symposium 5: The multilingual brain: interactions between several neurotransmitters during development, reward, and decision-making


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Investigation of the developmental downregulation and pathological upregulation of Vglut2 expression in DA neurons Willemieke M. Kouwenhoven1, Charles Ducrot1, Marie-Josee Bourque1, Jean-Francois Poulin2, Raj Awatramani2 and Louis-Eric Trudeau1 1: Department of Pharmacology, Physiology and Neuroscience, Universite de Montreal, Montreal, QC, Canada 2: Department of Neurology, Northwestern University, Chicago, IL, USA In Parkinson’s disease, the most vulnerable neurons are found in the substantia nigra (SN), while the adjacent dopamine (DA) neurons of the ventral tegmental area (VTA) are mostly spared. Although a significant subset of adult VTA DA neurons express Vglut2, a vesicular glutamate transporter, and release glutamate as a second neurotransmitter in the striatum, only very few adult SN DA neurons have this capacity. Our group and two recent papers demonstrated that lesions created by neurotoxins can upregulate the co-expression of Vglut2 in surviving DA neurons (Dal Bo et al., 2008; Steinkellner et al., 2018; Shen et al., 2018). We wonder which mechanisms regulate the expression of Vglut2 in DA neurons? Using an intersectional genetic lineage-mapping approach, based on Vglut2-Cre and TH-Flpo drivers, we first find that more than 98% of dopaminergic neurons expressed Vglut2 at some point in their embryonic development. Using fluorescent in situ hybridization, we have been able to refine that observation: already at E11.5 most DA neurons express Vglut2. Interestingly, at E14.5, subset-specific differences can be found, with Vglut2 transcript still found in caudomedial DA neurons, but with very limited expression in rostrolateral DA neurons. Moreover, we recently observed that post-natal DA neurons that were grown in presence of ventral striatal cells were more likely to co-express Vglut2 than DA neurons that were grown in presence of dorsal striatal cells (Fortin et al., 2018). These data suggest that striatal cells influence the neurotransmitter identity of DA neurons. Indeed, using our primary DA neuron-striatal co-culture system, in combination with single-cell qPCR, we observe that the presence of striatal cells increases the level of Th expression 2-fold in cultured post-natal DA neurons. Here, we propose that during development, striatal target cells provide a feedback to DA neurons that reaffirms their dopaminergic phenotype and represses their glutamatergic phenotype. Afferent regulation of prefrontal maturation during adolescence Kuei Y. Tseng, MD & PhD, University of Illinois at Chicago, Chicago, Illinois, USA Proper maturation of the prefrontal cortex (PFC) during adolescence is critical for the acquisition of cognitive abilities such as planning, decision-making and inhibitory control. Disruptions of these functions are often found in psychiatric disorders that emerge during adolescence including schizophrenia and substance use disorders. Yet, the neurobiology underlying the adolescent vulnerability remains unclear because of our limited understanding of the precise cell-circuit level mechanisms regulating the normative neuromaturational events occurring during this critical developmental period. To address this gap in knowledge, we compared the impact of diverse forms of environmental manipulations during adolescence and asked whether a disruption of prefrontal cortical maturation could contribute to the onset of psychiatric disorders that emerge during adolescence. Here I will present and discuss recent unpublished data to reveal how the gain of prefrontal GABAergic function is critical to sustain proper PFC capacity that ultimately affect PFC processing of afferent information and output. At the cellular level, such PFC maturation is associated with a state of reduced excitatory-to-inhibitory ratio in pyramidal output neurons, mainly due to a selective upregulation of local GABAergic inhibition. Interestingly, this gain of GABAergic function fails to occur in animals that underwent transient inhibition of the ventral hippocampus with DREADD. However, no deficits in PFC inhibition or excitatory-to-inhibitory balance were observed when DREADD-mediated hippocampal inhibition was delivered during late adolescence (P50-55) or adulthood (P75-80). Similarly, downregulation of prefrontal


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PV during adolescence was sufficient to elicit the same extent of GABAergic deficit as seen with DREADD. Collectively, these results indicate that ventral hippocampal afferent disruption during early and mid-adolescence had the most potent and enduring impact on PFC GABAergic function and maturation. As fine-tuning of PFC output is highly dependent on the activity of local GABAergic function, its disruption during adolescence is expected to elicit enduring deficits in PFC-dependent cognitive functions. Regulation of reward and habits by cholinergic interneurons from the striatum Mathieu Favier1, Helena Janickova2, Ornela Kljakic2, Erika Vigneault1, Marco A.M. Prado2, Vania F. Prado2 and Salah El Mestikawy1. 1Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, H4H 1R3, Canada. 2Robarts Research Institute, Molecular Medicine Laboratories, Department of Physiology and Pharmacology and Department of Anatomy & Cell Biology, The University of Western Ontario, 1151 Richmond St. N, N6A 5B7, London, ON, Canada The striatum regulates functions as diverse as locomotor activity, reward- and goal-directed behaviors or habits. Cholinergic interneurons (ChIs) are pivotal for the regulation of the striatal network. However, the precise role of ChIs in the striatum is poorly understood. This probably results from the fact that ChIs express the vesicular acetycholine transporter (VAChT) as well as the atypical vesicular glutamate transporter VGLUT3 and consequently communicate with acetylcholine and glutamate. To study the respective roles of acetylcholine (ACh) and glutamate (glut) cotransmission, we selectively deleted VAChT (VAChcKO mice) or VGLUT3 (VGLUT3cKO mice) to silence respectively ACh or glutamate (released by ChIs) in the striatum. We then investigated how ablation of VAChT or VGLUT3 from ChIs impacted on reward behaviors or on the goal-directed/habits balance. Interestingly silencing ACh had little effects on rewards [1] whereas silencing glutamate released by ChIs markedly increased rewarding properties of cocaine [2] and amphetamine [3]. In addition, we recently investigated the function of ACh/glutamate co-transmission in the regulation of goal-directed/habits balance. Symmetrically to what was found for reward-guided behavior, silencing glutamate had little impact on habits formation whereas VAChTcKO mice developed excessive habits. Interestingly, VAChTcKO mice showed increased vulnerability to models of eating disorders such as sucrose-binge eating and activity-based anorexia. These data suggest that ACh and glutamate are differentially used to regulate various striatal function. Our findings open new ways to treat severe pathologies such as addiction, anorexia or bulimia. 1. Guzman, M.S., et al., Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission. PLoS Biol, 2011. 2. Sakae, D.Y., et al., The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. Mol Psychiatry, 2015. 3. Mansouri-Guilani, N., et al., VGLUT3 gates psychomotor effects induced by amphetamine. J Neurochem, 2018. Dorsal raphe combinatorial serotonin-glutamate neurons drive reward by establishing excitatory synapses on VTA mesoaccumbens dopamine neurons Hui-Ling Wang1, , Shiliang Zhang1, Jia Qi1, Huikun Wang1, Roger Cachope2, Carlos A Mejias-Aponte1, Jorge A. Gomez3, Gabriel Mateo Semidey1, Gerard M. J. Beaudoin3, Carlos A. Paladini3, Joseph F. Cheer2 and Marisela Morales1, 1 National Institute on Drug Abuse, Neuronal Networks Section, National Institutes of Health, Baltimore, Maryland, USA. 2 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.3 Department of Biology, University of Texas at San Antonio, USA Dorsal raphe (DR) serotonin neurons provide a major input to ventral tegmental area (VTA). In the present study, we examined the ultrastructural and molecular characteristics of the synaptic connectivity between DR serotonin neurons and VTA dopamine neurons, and determined the role of these synapses in behavior. (1) By ultrastructural studies, we found that DR serotonin neurons


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(expressing serotonin transporter, SERT) establish both symmetric and asymmetric synapses on VTA dopamine neurons. (2) Surprisingly, we found that axon terminals from DR-SERT neurons that make asymmetric (putative excitatory) synapses on VTA dopamine neurons co-express vesicular glutamate transporter 3 (VGluT3, transporter for accumulation of glutamate into synaptic vesicles). These findings suggest that a subset of DR dual SERT-VGluT3 neurons establish excitatory synapses on VTA dopamine neurons. (3) By tract tracing approaches, we found that dual SERT-VGluT3 neurons establish asymmetric synapses on VTA dopamine neurons that innervate the nucleus accumbens (nAcc), suggesting that release of glutamate from SERT-VGluT3 terminals have the capabilty to activate mesoaccumbens dopamine neurons. (4) By VTA photoactivation of fibers from DR-SERT neurons, we found that this activation elicits excitation of mesoaccumbens dopamine neurons, induces release of dopamine in nAcc, and promotes conditioned place preference (CPP). (5). Because we have previously demonstrated nAcc dopamine release and a robust reinforcing effect by VTA glutamate release from DR VGluT3-fibers (Qi et al., 2014. Nat Comm), we compared these effects with those mediated by DR SERT-fibers. We found that the amount of dopamine release and CPP induced by VTA activation of SERT-fibers are lower than those induced by activation of VGluT3-fibers. However, CPP induced by activation of SERT- fibers is more resistant to extinction when compared to the CPP induced by activation of VGluT3- fibers.


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Saturday, June 15, 2019 Abstracts for Oral Presentations

CCNP Young Investigator Award Lecture Interaction between current stress and genome-wide methylation in conferring risk for suicidal ideation Vincenzo de Luca, Centre for Addiction and Mental Health, Toronto, ON Background and Aims: In this study, we investigate the molecular mechanisms mediating the effect of stress in triggering current suicidal ideation. Stress represents a major risk factor for completed suicide. However, how this change affects gene expression in conferring risk for suicide is not clear. DNA methylation is a form of epigenetic modification that regulates gene expression. Our primary aim is to investigate the role of genome-wide methylation in conferring risk for current suicidal ideation (SI) in 107 patients with schizophrenia. Methods: The presence of current SI and genome-wide methylation patterns hase been assessed in 107 patients with schizophrenia. DNA methylation has been measured in white blood cells as a possible peripheral biomarker of SI. SI is the primary outcome variable in a logistic regression model including methylation status of white blood cells using the Illumina 450 array. Results: We have analyzed the effect of genome-wide methylation levels in a sample of 107 schizophrenia subjects (19 with current SI and 88 without current SI) and we found that higher methylation level in the CpG cg06121808 on chromosome 2 was associated with current SI (p= 0.000003; OR: 1.3 95% CI=1.1-1.4). Conclusions: Thus, molecular biomarkers could advance our understanding of the molecular mechanisms of stress-related SI. Furthermore, the methylation sites that we have identified should be replicated in other suicide related phenotypes to generate robust biomarkers with high translational value providing proxy outcome measures in proof of concept interventions aiming at reducing SI.

Symposium 6: Hippocampal mechanisms underlying depression vulnerability and

treatment

Sex specific neural signatures of stress-induced behavioral adaptation Jessie Muir, Rosemary C. Bagot McGill University, Montreal, QC Epidemiological data indicates stress is a major factor risk factor associated with development of depression, yet not everyone reacts to stress the same way. Factors such as biological sex and early life adversity are associated with increased risk for depression. Identifying mechanisms of increased vulnerability may help develop targeted treatments and strategies for prevention. We previously identified pre-existing differences in nucleus accumbens (NAc) activity that associate with resilience to chronic social defeat stress (CSDS), an animal model for depression, suggesting that baseline differences in neural activity may influence future susceptibility even in the absence of other identified risk factors. In this work, we used fiber photometry to record activity in the glutamatergic inputs from the ventral hippocampus (vHIP) to the NAc during tests of depressive-like behavior both before and after chronic stress. Stimulation of this pathway following stress has previously been shown to increase susceptibility to CSDS but it is not known if such differences are cause or consequence of susceptibility. Our present findings identify novel sex-specific


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differences in vHIP-NAc signaling that may predict behavioral adaptation to following chronic stress. Hippocampal negative memory engrams enhance stress susceptibility Tian Rui Zhang, Amanda Larosa, Marie-Eve Di Raddo, Vanessa Wong, Alice S. Wong and Tak Pan Wong, McGill University, Montreal, QC The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor. Compared to resilient and non-stressed control mice, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e. engram cells) in both the dorsal and ventral hippocampal CA1 regions. The density of CA1 engram cells correlated with the level of social avoidance. Susceptible mice exhibited more negative stimuli-, but not neutral stimuli-, related CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. Our findings reveal that the susceptibility to CSDS is regulated by hippocampal CA1 engrams for negative memory. Hippocampal negative memory engrams may underlie the vulnerability and expression of cognitive symptoms in depression. Molecular and neural circuit mechanisms underlying antidepressant treatment resistance Mark Gergues, Christine Yohn, Marjorie Levinstein, Benjamin Samuels, Rutgers University, New Jersey, USA Approximately 32-35 million adults in the US population (16%) experience an episode of major depression in their lifetime, and commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Given that antidepressants such as SSRIs are also commonly used to treat other psychiatric disorders, such as generalized anxiety disorder and obsessive-compulsive disorder, it is of critical importance to determine the differences between remitters and non-remitters to antidepressant treatment. Our overall research program addresses this question by assessing antidepressant treatment resistance in mice. Here we will show that both molecular and neural-circuit based approaches to modifying the dentate gyrus may be able to convert behavioral non-responders to fluoxetine (a SSRI) into responders. Specifically, we will show that both Activin signaling based modifications of dentate gyrus and silencing of mature dentate gyrus granule cells can alter the behavioral response to fluoxetine. Searching for exercise mimetic to improve stress resilience using animal models Sonata Suk-yu Yau, Hong Kong Polytechnic University, Hong Kong


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Depressive disorders are the second leading cause of disability worldwide. There remain significant limitations of current antidepressant medication treatment, including delayed therapeutic effect, drug-resistance and high remission rates. Non-pharmacological strategies such as exercise interventions that can enhance stress resilience and may critically reduce the incident rate of depression. Our previous work has demonstrated that adiponectin (a fat cell secreted hormone for regulating metabolism) is a key mediator for physical exercise to elicit its antidepressant effect via promoting hippocampal neuroplasticity. In this talk, I will highlight the underlying mechanisms of how physical exercise enhances stress resilience by promoting hippocampal neuroplasticity. I will also talk about the latest findings on AdipoRon, an adiponectin receptor agonist, as a potential exercise mimetic to promote hippocampal function. CCNP Innovations in Neuropsychopharmacology Award Lecture

Does the Netrin-1 pathway guide resilience and susceptibility in adolescence? Cecilia Flores, McGill University, Montreal, QC Adolescence is an age of heightened vulnerability to mental health conditions. Yet, there is a significant gap in our knowledge about basic mechanisms of adolescent brain development and about how they are influenced by experience, including drugs of abuse and stressors. This talk focuses on the emerging role of guidance cues and their microRNA regulators in adolescent brain development and in its implications for psychiatric susceptibility and resilience. I discuss recent findings from rodent and human studies on cellular and molecular mechanisms underlying the development of the prefrontal cortex and how these processes are altered by adverse and perhaps even positive experiences. I emphasize how this new line of research can have significant implications for the development of data-driven prevention and intervention strategies for the youth.


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Poster Session I – Thursday June 13, 2019 17:30 – 19:30 – Restaurant, Basement Level

1. Measurement-based care (MBC): validation of the clinical global impressions (CGI)

scale in the context of a first episode psychotic disorder program (FEP) Michelle Khau, BSc, Patricia Boksa. PhD, Karim Tabbane. MD/ PhD, Ridha Joober. MD/ PhD Integrated Program of Neuroscience, McGill University, Montreal, Quebec, Canada Introduction: In psychiatric care, treatment initiation and maintenance relies mostly on qualitative descriptions of diagnostic evaluations and symptoms. Unfortunately, this practice may complicate illness progression tracking, leading to poor adherence to treatment guidelines and therapeutic inertia. It has been proposed that MBC may help to correct this problem. Measurement-Based Care (MBC) involves rating scales among other quantitative data to guide clinical decision-making but may be time-consuming and pose other challenges for psychiatric disorders (e.g. lack of symptom insight). However, the Clinical Global Impressions (CGI) Scale is a simple, rapid to administer assessment tool that has received widespread validity and utility in clinical trials for schizophrenia. In this study, we present preliminary data suggesting its validity in day-to-day practice in the context of FEP. Methods: 76 patients were included in this study. Individual CGI of Severity of Illness were completed by clinicians at 12 and 18 months. Well-established scales assessing positive symptoms (SAPS), negative symptoms (SANS), psychotic and other symptoms (BPRS), and global functioning (GAF) were completed by case evaluators within a short time interval of the CGI-S. Bivariate Pearson correlations were conducted between the CGI-S and the aforementioned scales. Results: Especially in month 12, CGI-S correlations were significant and strongest with the BPRS (r = 0.552), GAF (r = 0.530), and SAPS (r = 0.521) but at both time points the CGI-S was least correlated with the SANS (m12 -r = 0.401; m18 -r = 0.036). Conclusion: While the aforementioned scales individually reflect aspects of a patient’s clinical situation in treatment for FEP, the CGI alone coherently reflects it just as well. We propose that the systematic use of this simple and quick to administer tool may improve the quality of care and adherence to therapeutic guidelines. However, as suggested by data, further improvements in capturing negative symptoms are needed.

2. Alcohol consumption in striatal Bmal1 knock-out mice Nuria de Zavalia, PhD; Pavel Solis; Gabrielle Parent; Sarah Ferraro; Konrad Shöttner, PhD; Milan Valyear; Nadia Chaudhri, PhD; Shimon Amir, PhD Centre for Studies in Behavioural Neurobiology, Psychology Department, Concordia University, Montreal, QC, Canada Alcohol exposure affects brain areas and neuronal circuits related to habit formation and decision-making in a complex and poorly understood manner. The dorsal striatum is of particular interest as it is implicated in the predisposition of alcohol consumption. Recent evidences have demonstrated important links between the core clock genes, Bmal1 and Per2, and excessive alcohol consumption. Bmal1 and Per2 are transcriptional regulators and core components of the mammalian circadian clock, and are expressed in most brain regions and cell types, including the GABAergic medium spiny projection neurons (MSNs) of the striatum. The aim of this work was to study ethanol consumption in mice containing a functional mutation in Bmal1 gene (using the Cre-loxP system) in the striatum. Wild type (WT) and Knock-out (KO) male and female mice were tested in: (A) 24 h intermittent ethanol access protocol (15%); (B) 24 h intermittent ethanol access protocol with ascending concentrations of ethanol (5-45%); (C) Sucrose preference protocol. Depletion of Bmal1 mRNA and protein was observed in the striatum of KO mice compared with WT mice. Bmal1 KO male mice drink significantly more alcohol and have a higher alcohol


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preference than WT mice (two-way ANOVA, n=10/group, P < 0.05). Bmal1 KO female mice drink less alcohol and have a lower alcohol preference than WT mice (two-way ANOVA, n=10/group, P < 0.05). No significant differences in sucrose consumption were observed. These preliminary results suggest a sex based difference in alcohol-related Bmal1 function in the striatum. A protective role of Bmal1 against alcohol intake was observed only in male mice.

3. Prefrontal circuit reorganization in a mouse model of schizophrenia Moushumi Nath; Sanjeev K. Bhardwaj, PhD; Tak Pan Wong, PhD, Lalit K. Srivastava, PhD Author Affiliations: Department of Psychiatry, Douglas Hospital Research Centre, McGill University, Montreal, Quebec, Canada Introduction: The hippocampal-prefrontal cortical pathway mediates cognitive behaviours; dysfunction in this pathway is associated with cognitive deficits in schizophrenia. Our objective is to decipher the mechanisms by which this pathway develops in order to understand how maladaptive cognitive behaviours may emerge: we hypothesize that hippocampal inputs play a critical role in structuring the prefrontal cortex by modulating the functional properties of parvalbumin-interneurons during their protracted maturation period; this altered prefrontal cortical structure may mediate cognitive deficits. Methods: To determine whether and how hippocampal inputs may influence parvalbumin-interneuron function, we bilaterally lesioned the ventral hippocampus in neonatal two-week old mice, and subsequently examined the functional properties of mature prefrontal cortical parvalbumin-interneurons in five-week old mice. To characterize parvalbumin-interneuron function, we visually identified these interneurons using transgenic mice in which the parvalbumin-interneurons express tdTomato, and characterized the spiking properties and postsynaptic activities of these interneurons through whole-cell ex vivo slice recordings. Results: Our results indicate that abolishing hippocampal inputs to the prefrontal cortex in neonatal mice results in the altered maturation of parvalbumin-interneurons. These interneurons show a failure to sustain high frequency firing (p<0.05), and show a deficit in the NMDA receptor mediated postsynaptic currents (p<0.05). These effects were observed in male, but not female, mice. No significant differences were observed in resting membrane potential, action potential properties, action potential threshold, and AMPA receptor mediated postsynaptic activity. Conclusion: Hippocampal inputs influence the maturation of prefrontal cortical parvalbumin-interneurons. A deficit in inputs results in decreased sustained firing frequencies. Deficits in NMDA receptor currents in interneurons are corroborated with the proposed impairment of PV neuronal function after neonatal ventral hippocampal lesion. Reduced PV neuronal activity may contribute to the respective emergence of attentional and learning cognitive deficits observed in schizophrenia.

4. Cumulative exposure to ADHD medication is inversely related to hippocampal sub-regional volume in children with ADHD

Nellie H. Fotopoulos1,2, Gabriel A. Devenyi1,3, Stephanie Guay4, Sarojini M. Sengupta1,3, Sherif Karama1,3,6, M. Mallar Chakravarty1,3,7, Natalie Grizenko1,3, and Ridha Joober1,2,3,5

1Douglas Mental Health University Institute, Montréal, Québec, Canada 2Department of Human Genetics, McGill University, Montréal, Québec, Canada 3Department of Psychiatry, McGill University, Montréal, Québec, Canada 4Faculty of Dentistry, McGill University, Montréal, Québec, Canada 5Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada 6Montréal Neurological Institute, Montréal, Québec, Canada 7Department of Biological and Biomedical Engineering, McGill University, Montréal, Québec, Canada


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Background: Although there is evidence for a normalization of brain structure following psychostimulant use, literature on the effects of duration and dose of chronic psychostimulant use on the brain is scarce. Here, we investigated the effects of cumulated exposure to medication (range 1 week to 4.69 years) on cortical and subcortical structures in a clinical sample of chronically-treated children with ADHD (n=109). Methods: Cumulative exposure to ADHD medication was defined as the product of duration on medication (days) and dose (mg/day), yielding the area under the curve. RMINC, CIVET-1.1.12 and MAGeT-Brain were used to perform linear modelling, acquire cortical thickness and surface area measurements, and obtain subcortical volumes in 51 regions, respectively. Multiple-testing correction using FDR was performed. Results: Significant effects of medication exposure were found in 2 subregions of the left hippocampus, the CA1 (df=101; q=0.0083) and the strata radiatum/lacunosum/moleculare (df=101; q=0.0083). A trend was found in the CA1 region of the right hippocampus (df=101; q=0.0712). Children with a higher cumulative exposure to ADHD medication were associated with reduced hippocampal volumes. Regions remained significant after controlling for ADHD symptom severity. No effects of medication exposure were detected on cortical structures. Conclusions: Although this study is cross-sectional, the findings suggest that prolonged psychostimulant use at higher doses alters hippocampal volume in subregions important for episodic memory function in children with ADHD. If reproduced in an independent sample, such findings may have important clinical implications in ADHD treatment management.

5. Using a novel artificial intelligence technique to model development of side effects in response to treatment in children with ADHD: a theoretical framework

Sarojini M. Sengupta PhD1,2, Barbara Barth1,2, Anton Malkhveitchouk, Patricia Pelufo Silveira MD1,2 PhD, Marie-Ève Fortier PhD1, Natalie Grizenko MD, FRCPC1,2, Ridha Joober MD, PhD 1,2,3,4, Raja Sengupta PhD 5, 6 Author affiliations: 1. Douglas Mental Health University Institute 2. Department of Psychiatry, McGill University 3. Department of Human Genetics, McGill University 4. Integrated Program in Neuroscience, McGill University 5. Department of Geography, McGill University 6. School of Environment, McGill University Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a complex and highly prevalent psychiatric disorder among school-aged children. The first line of treatment are psychostimulants, particularly methylphenidate [MPH]. Significant variability has been observed in terms of response to treatment. The objective of this study is to model this variability, using a novel computational technique that is designed to study complex systems. Methods: A complex systems model of specific neurochemical pathways has been built using STELLA®, to simulate the pathways that influence the response to MPH treatment. Results: A basic model of interconnected dopaminergic and norepinephrine pathways has been built to simulate each step that follows the ingestion of MPH, from the absorption in the liver, to the site of action at the dopamine (DA) and norepinephrine (NE) transporters in the brain, to each of the downstream steps involved after the release of DA and NE into the synaptic cleft. This preliminary model begins to capture the interconnectedness between individual chemical pathways at multiple temporal scales. Conclusion and future directions: The running of this basic model serves as a first step to predict response to MPH treatment. Work is ongoing to expand this basic model by giving a weight to each node. This weight will be determined by using a gene-based association method called PrediXcan. Using elastic net solutions, this algorithm estimates the component of gene expression determined by the genetic profile, “imputing” gene expression from the genotype information. The genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome datasets. The primary “emergent properties” in the model are response to treatment. The model is being validated with data that has been collected in the prospective double-blind placebo-controlled pharmaco-behavioural


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genetic study conducted with 880 children with ADHD over the past 20 years, funded mainly by CIHR (PIs: RJ and NG).

6. Linking increased chronic stress-related memory and stress susceptibility in an animal model of depression

Amanda Larosa,BSc1,2, Jennifer Siu2, Tian Rui Zhang,MSc1,2, Alice S Wong1, Tak Pan Wong,PhD2,3 1Dept. Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada 2Neuroscience Division, Douglas Hospital Research Centre, Montreal, Quebec, Canada 3Dept. Psychiatry Introduction: Cognitive changes, specifically a bias towards the encoding and recall of memories of negative events exists in depression and have been suggested to underlie the vulnerability to depression. We proposed that the hippocampus, especially the dorsal CA1 hippocampal subregion, presents as a promising region of interest— linking the effects of chronic stress with cognitive changes in depression. Method: We used the UCLA miniscope to examine activities of dorsal CA1 neurons in C57 mice that are susceptible to a chronic stressor called social defeat. Through a lens implanted in the hippocampus, the miniscope records fluorescent calcium activity as a proxy for neuronal activation. The susceptibility to chronic social defeat stress (8 daily episodes of social defeat by an aggressive CD1 mouse) was determined by a social interaction test, where susceptible mice express avoidance of a social encounter with the aggressor. We examined the progressive change of the activity of individual dorsal CA1 neurons during chronic stress. Finally, non-stressed mice and defeated mice that are resilient to chronic social defeat stress were used as controls. Results: As the chronic stress paradigm progressed, increased calcium spiking frequency in the dorsal CA1 was observed in susceptible animals. Surprisingly, spiking frequency was similar to resilient and control animals at the start of defeat, but this progressive increase reached significance on the last defeat day (5th defeat, p=0.01; 8the defeat, p=0.04). Moreover, neurons which were active during stress were significantly reactivated on subsequent stress days in susceptible animals (p=0.03). Conclusion: Stress susceptibility is potentially due to increased activity of defeat-related neurons and the recall of the defeat memory. Enhanced effectiveness of forming chronic stress-related social memory could be a cellular mechanism for stress susceptibility and the vulnerability to depression.

7. Optogenetic activation of the infralimbic cortex to nucleus accumbens shell circuit attenuates the renewal of appetitive Pavlovian responding

Franz R. Villaruel, BSc; Melissa Martins; Nadia Chaudhri, PhD. Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Introduction: Neural activity in the infralimbic cortex (IL) is implicated in suppressing appetitive Pavlovian conditioned responding after extinction. The present study tested whether this inhibition of appetitive responding is mediated by specific projections of the IL to the nucleus accumbens shell (NAcS). Methods: Male, Long-Evans rats received unilateral intra-IL microinjections of a viral vector encoding channelrhodopsin with enhanced yellow fluorescent protein (ChR2-eYFP) or eYFP alone, and were implanted with an optical fibre targeting the ipsilateral NAcS. Following surgery, rats received Pavlovian conditioning in a distinct context (Context A) in which a conditioned stimulus (CS; 10 s white noise) was paired with the delivery of 10% sucrose in a fluid port. Next, rats received extinction in a different context (Context B) in which CS trials occurred without sucrose. Rats were then tested in context A and B (counterbalanced). Tests occurred without sucrose and CS presentations were paired with optical IL-to-NAcS stimulation. Results: Renewal of appetitive Pavlovian responding was observed at test in the eYFP but not the


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ChR2-eYFP group. In the eYFP group, responding to the CS was greater in the renewal context (context A) than the extinction context (context B) as measured by frequency, latency, duration, and probability of CS-elicited port entries. In the ChR2-eYFP group, activation of the IL-to-NAcS projection reduced renewal of CS-elicited port entries in context A and did not affect responding in context B. Additional tests, revealed that IL-to-NAcS activation also reduced reacquisition in Context A, and novel CS acquisition. Conclusions: This study demonstrates the importance of the IL-to-NAcS circuit in suppressing the renewal and reacquisition of appetitive Pavlovian responding. Activation of the IL-to-NAcS may suppress responding by facilitating the recall of an extinction memory. Additional research is needed to test whether the IL-to-NAcS circuit is also involved in acquisition of appetitive Pavlovian responding.

8. A transcriptomic analysis of the effect of haloperidol in wild type and Nur77 (Nr4a1) deficient rats: identification of a role for dual specificity phosphatase 5 (Dusp5) in antipsychotic drug effects

Simon Majeur1, Giovanni Hernandez1, Fatéma Dodat1, Jean-Alexandre Caissy1, Emilie Legault1, Claude Rouillard2 and Daniel Lévesque1 1 Faculté de Pharmacie; Université de Montréal, Montréal, Qc, Canada; 2 Axe Neuroscience, Centre de Recherche du CHU de Que´bec, and Dept. Psychiatrie & Neuroscience, Fac. de médecine,Universite´ Laval, Qc, Canada Introduction: Nur77 (Nr4a1) is a transcription factor of the nuclear receptor family that is associated with dopamine neurotransmission. In particular, we showed that Nur77 expression/activity modulated haloperidol-induced motor effects (catalepsy, tardive dyskinesia). But, the mechanism of action of Nur77 over dopamine-mediated effects remains elusive. Methods: To evaluate the role of Nur77 in antipsychotic drug effects, we compared striatal gene transcript (mRNA) levels following a single dose of haloperidol (0.5 mg/mg, i.p.) in wild type and Nur77-deficient rats using Next Generation gene Sequencing (RNAseq) with a coverage of about 33 million paired-end reads per sample (Hiseq2000) followed by bioinformatic analysis (GeneCards suite). We selected a series of transcripts for validation using RT-qPCR. We also compared the modulation of Dusp5 protein levels using Western blots in non-human primates chronically exposed to haloperidol (N=10) clozapine (N=5) or untreated controls (N=5). Results: Statistical analysis indicates that multiple genes were down- or up-regulated by haloperidol and a subset of these genes were differentially modulated between wild type and Nur77 deficient rats exposed to haloperidol. Matching score statistics using GeneAnalytic analysis revealed high score matches of modulated transcripts with biological process, molecular function, pathways and diseases consistent with striatal dopamine signaling pathways. Amongst significantly modulated transcripts, we identified dual specificity phosphatase 5 (Dusp5) mRNA as a very interesting candidate. We confirmed the modulation of Dusp5 in antipsychotic drug effects in non-human primates chronically exposed to haloperidol or clozapine. Interestingly, Dusp5 protein levels were down-regulated in clozapine-treated monkeys as well as in haloperidol-treated animals, which did not develop tardive dyskinesia (TD) (N=5), compared to the haloperidol-treated group that develop TD (N=5) or control group. Conclusions: This transcriptomic analysis in a transgenic rat model identified, for the first time, a putative Nur77-dependent modulation of phosphatase Dusp5 as a new signaling component associated with antipsychotic drug-induced abnormal involuntary movements.

9. Glutamate N2C NMDA receptors relay the reward signal in the ventral tegmental area Giovanni Hernandez, PhD 1 Poirier Emmanuelle BSc; 1 Lebied Karim BSc 1 Kouwenhoven, Willemieke M PhD 2 Lévesque, Daniel PhD, 3 Rompré, Pierre-Paul PhD. 1 (1) Département de neurosciences (Faculté de médecine), (2) Département de pharmacologie et physiologie (Faculté de médecine), (3) Faculté de Pharmacie; Université de Montréal, Montréal, QC., Canada


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Introduction: Studies on how the reward signal is transmitted in the brain had identified glutamate neurotransmission as an important component in the reward circuitry. Glutamate (Glu) relays the reward signal from the dorsal raphe to ventral tegmental area (VTA) dopamine (DA) neurons. It controls the switch from tonic to phasic firing in active DA neurons, the latter being associated with reward signaling. Also, Glu plays a role in the maintenance of DA inhibitory drive. This myriad of roles suggests that different Glu receptors are involved in these different functions. Here we studied the effects of VTA down-regulation of GluN2C-containing NMDA receptor on the reward signal that arises from dorsal raphe (DR) electrical stimulation. Methods: After rats were implanted with an electrode aimed at the DR and bilateral cannulae aimed at the VTA, they were trained to self-stimulate, and reward thresholds were measured using the curve-shift paradigm. Once stable behavioral measurements were obtained, small interfering RNA (siRNA) against GluN2C subunit or a non-active RNA sequence was microinjected into the VTA (5 µg per side); 24 h after each of the 2 consecutive daily bilateral VTA microinjections, reward thresholds were obtained. After the last measurement, reward thresholds were reassessed once rats received a bilateral VTA microinjection (0.825 nmol/0.5 µl/side) of the NMDA receptor antagonist, PPPA. Brains were harvested, and processed for fluorescent in situ hybridization and/or western-blot. Results: The siRNA treatment produced a selective down-regulation of the GluN2C subunit (?40%) and a significant reduction in reward pursuit. There is an overlapping of TH+ and GluN2c in the VTA. Interestingly, the NMDA antagonist PPPA enhanced reward pursuit only in those rats that received the non-active RNA sequence. Conclusion: The present results suggest that VTA Glu neurotransmission relays the reward signal initiated by DR electrical stimulation by acting on GluN2C-containing NMDA receptors.

10. Neural correlates of extinction in a rat model of appetitive Pavlovian conditioning Alexa E. Brown, BA Franz R. Villaruel,BSc Nadia Chaudhri,PhD Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, QC, Canada Introduction: Extinction is a fundamental form of inhibitory learning that is important for adapting to changing environmental contingencies. In aversive Pavlovian conditioning procedures, the infralimbic cortex (IL) has been identified as a central hub for extinction learning. However, little is known about the neuronal correlates and networks that mediate the extinction of responding to appetitive cues. In the present study, we used Fos immunoreactivity to determine whether the IL and other connected brain regions are activated following extinction of Pavlovian responding to a sucrose-predictive cue. Methods: Briefly, male, Long-Evans rats received 8 daily, 57 min Pavlovian conditioning sessions, in which 10 trials of a CS (20 s white noise) occurred on a 280 s variable-time schedule. In the paired group, CS trials co-terminated with delivery of 10% sucrose (w/v) into a fluid port for oral consumption (0.3 mL/CS, over 10 s). Control groups also received CS presentations; however, sucrose was delivered either during the ITI (unpaired) or in the home-cage. After conditioning, 1 or 6 extinction sessions were conducted wherein the CS was presented but sucrose was withheld. Thirty min after the end of the final extinction session, rats were deeply anesthetized, transcardially perfused, and their brains processed for Fos immunoreactivity. Results: Preliminary data indicate greater Fos immunoreactivity in the IL and prelimbic cortex (PL) of paired and unpaired groups in comparison to home-cage controls. However, Fos expression in the IL, but not the PL, was elevated after one extinction session compared to six extinction sessions. Conclusion: These data suggest that the IL is important in early extinction learning to appetitive cues. Ongoing studies are examining other candidate areas such as the nucleus accumbens, amygdala, and other cortical subregions in order to determine a network of brain regions that are involved in extinction of appetitive Pavlovian conditioning.


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11. Excitatory context conditioning promotes the reinstatement of appetitive Pavlovian conditioning

Mandy R. LeCocq, BA & Nadia Chaudhri, PhD Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, QC, H4B 1R6, Canada Introduction: Context plays a dynamic role in promoting relapse-like behaviours. Here, we examined the role of excitatory context conditioning in the reinstatement of responding to a sucrose-predictive cue. Methods: Rats (male, Long Evans, Charles River) received 12 Pavlovian conditioning sessions in which presentation of a lever conditioned stimulus (CS; 20s) co-terminated with the 10s delivery of sucrose (10% w/v) into a fluid port (8 CS trials/session; VT 280s; 2.4 mL/session). Eight extinction sessions followed, in which the CS was presented without sucrose. Rats then received non-contingent exposure to sucrose in the fluid port, as during Pavlovian conditioning but without CS presentation. Next, separate groups received either 4 sessions of exposure to the context in which sucrose had been delivered, or 4 sessions of exposure to an alternate context, followed 24 h later by a non-reinforced test for reinstatement. A third group received this reinstatement test 24 h after non-contingent sucrose exposure. Results: Prior exposure to sucrose reinstated CS port entries at test 24 h later, and at test following repeated exposure to the alternate context. However, reinstatement was significantly attenuated following exposure to the context in which sucrose had been delivered in. In a subsequent experiment, rats received Pavlovian conditioning and extinction as before, but in a distinct context (Context A). Next, separate groups received non-contingent sucrose exposure in Context A or a different context (Context B), followed 24 h later by a reinstatement test in Context A. Prior exposure to sucrose reinstated CS port entries 24 h later when sucrose was presented in either context. However, reinstatement of port entries during the inter-trial interval was significantly attenuated following exposure to sucrose in Context B. Conclusions: These findings suggest that an excitatory association between sucrose and the context in which sucrose is delivered in is critical in driving reinstatement.

12. Augmenting mesolimbic dopamine is not sufficient to elevate responding to an alcohol predictive signal

Milan D. Valyear, MSc Soraya Lahlou, BA Ghislaine Deyab Alexa Brown, BA Nina Caporicci-Dinucci Iulia Glovaci, PhD Andrew Chapman, PhD Nadia Chaudhri, PhD Introduction: Responding triggered by a discrete alcohol-predictive conditioned stimulus (CS) is elevated in a context associated with alcohol intake relative to a neutral context, and this elevation requires activity in the dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS). Here, we determined if activating VTA dopamine neurons or their projections to the NAcS was sufficient to elevate responding to a discrete alcohol CS. Methods: In male, transgenic TH::Cre rats expressing hM3Dq designer receptors in the VTA, we tested responding to a discrete alcohol-predictive CS. hM3Dq was expressed exclusively on TH+ neurons and activated by clozapine-n-oxide (CNO; 10 mg/kg i.p.) or clozapine (.1 mg/kg i.p.). Results: Systemic administration of CNO or clozapine before test had no impact on CS responding. However, consumption of standard chow under conditions of mild food restriction was reduced by both ligands, showing that our chemogenetic manipulation was effective. In a separate study, we predicted that selectively augmenting activity in the VTA-to-NAcS pathway would increase CS responding. However, administration of CNO directly into the NAcS (0 or 3 mM, .3 µl/hemisphere) had no impact on responding to the CS. Using in-vitro electrophysiology we confirmed that CNO-activation of hM3Dq on dopaminergic processes in the nucleus accumbens increased the amplitude of electrically-evoked postsynaptic potentials in medium spiny neurons. Conclusions: Together with our previous research these data suggest that activity in the VTA-to-NAcS projection is necessary, but not sufficient, for the elevation of responding to an alcohol CS


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in an alcohol context. Rather than driving CS responding directly, dopaminergic input to the NAcS may modulate the activity of other NAcS inputs (e.g., ventral hippocampus) that are recruited by alcohol contexts to elevate CS responding.

13. Chronic desipramine-induced noradrenergic neuroplasticity and recovery of anxiety and depression phenotypes in a fluoxetine-resistant mouse model

Faranak Vahid-Ansari, Amin Zahrai, Mireille Daigle, Paul R. Albert OHRI (Neuroscience), UOttawa Brain and Mind Research Institute, Ottawa, ON, CA Introduction: Alterations in serotonin (5-HT) have been implicated in major depressive disorder, for which 5-HT reuptake inhibitors (SSRIs) are the first-line treatment. However, many patients fail to respond and are switched to augmentation or other antidepressants like tricyclic-antidepressants (TCAs) on a trial and error basis. To elucidate which strategies can overcome SSRI resistance, we generated the cF1ko mice, in which the repressor Freud-1 is deleted in adult 5-HT cells (Vahid-Ansari et al., 2017). The cF1ko mice have increased 5-HT1A autoreceptor levels, function, and a fluoxetine-resistant anxiety/depression phenotype. Here we address the response of cF1ko mice to the TCA desipramine, targeting 5-HT and noradrenaline systems. Methods: cF1ko mice were treated chronically with desipramine, examined using validated behavioral tests including elevated-plus maze, open-field, novelty-suppressed feeding, forced-swim and tail-suspension. Immunofluorescence for the norepinephrine transporter (NET) detected brain-wide projections of the noradrenaline system. Co-immunofluorescence for FosB/GAD67, FosB/CaMKII/VGluT1-2 was used to detect brain-wide chronic activity of GABAergic or glutamatergic neurons. Results: Chronic desipramine treatment reversed the depression/anxiety phenotypes of cF1ko mice associated with the higher activity of noradrenaline cells residing in locus coeruleus comparing to vehicle treatment. Chronic desipramine treatment selectively inhibited the activity of interneurons in the target areas of medial prefrontal cortex (mPFC) and amygdala (BLA). In addition, successful treatment with chronic desipramine induced recovery in NE projections in mPFC and BLA. Conclusion: The induction of 5-HT1A autoreceptors in cF1ko mice was associated with global changes in the corticolimbic circuitry implicated in depression and anxiety. In contrast to fluoxetine, chronic desipramine treatment selectively target interneurons associated with reversed NET expression in mPFC and BLA. These results suggest that desipramine may overcome the SSRI resistance phenotype by directly targeting 5-HT-responsive cells. In summary, the cF1ko mice provide a clinically relevant genetic model of SSRI-resistance to investigate the efficacy and mechanisms of alternative antidepressant approaches.

14. Effects of dopamine receptor antagonism and amphetamine sensitization on sign- and goal-tracking after extended training

Shaun Y.-S. Khoo, PhD, Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada. Alexandra Uhrig, Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada. Nadia Chaudhri, PhD, Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada Introduction: Dopamine is initially important for sign-tracking, where motivational value is assigned to a conditioned stimulus (CS) for an appetitive unconditioned stimulus (US), but after extended training dopamine is required for goal-tracking. We tested the effects of selective dopamine D1-like and D2-like receptor antagonism on the expression of Pavlovian conditioned approach after extended Pavlovian conditioned approach (PCA) training. We also tested the hypothesis that amphetamine sensitization would accelerate the phenotypic shift to sign-tracking that is produced with extended training.


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Methods: 24 male Long-Evans rats were subjected to 20 PCA sessions in which one lever (CS+, 10 s) predicted 0.2 mL 10% sucrose delivery and a second lever (CS–) did not. Each 52 min session included 10 CS+ and 10 CS– presentations 80, 140, or 200 s apart. SCH-23390 or eticlopride were then administered prior to behavioral tests, where no sucrose was delivered, at doses of 0, 0.01, and 0.1 mg/kg (s.c.). In a second experiment, rats were exposed to vehicle or 2 mg/kg amphetamine (i.p.) for 7 days (n = 12/group). After a 10-day incubation period, they were subjected to PCA training for 16 sessions. Results: The D1 antagonist SCH-23390 reduced CS+ port entries and CS+ lever activations at both doses, but also reduced port entries during inter-trial intervals and open field locomotor activity. In contrast, 0.01 mg/kg eticlopride reduced CS+ port entries in goal-trackers, without affecting CS+ lever activations. At 0.1 mg/kg, eticlopride reduced inter-trial intervals port entries and locomotor activity. Amphetamine sensitization had no effect on the acquisition of sign-tracking. Conclusions: Blocking D1 receptors reduced goal- and sign-tracking after extended training, but also reduced locomotor behaviour. D2 receptors were not required for sign-tracking after extended training, but remained necessary for goal-tracking. The sensitivity of the dopamine system did not appear to drive acquisition of sign-tracking behavior.

15. Neurostructural correlates of glutathione peroxidase 3 rs3792797 polymorphism in adolescents with and without bipolar disorder

Yi Zou, B.Sc; Megan Mio, B.Sc; Mikaela Dimick, BA; Anahit Grigorian1, MSc; Lisa Fiksenbaum1, PhD; Bradley Maclntosh1,2, PhD; Benjamin I. Goldstein1,3, MD, PhD, FRCPC 1Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 2Heart and Stroke Foundation, Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, ON, Canada; 3University of Toronto, ON, Canada Introduction: Oxidative stress has been implicated in the etiopathology of bipolar disorder (BD). Relatedly, BD is among the most heritable, and therefore genetic, psychiatric disorders. However, no prior study has examined oxidative stress genes in relation to neuroimaging phenotypes in BD. We evaluated two oxidative stress genes, glutathione peroxidase 3 (GPX3) rs3792797 and super oxide dismutase 2 (SOD2) rs4880, in relation to structural neuroimaging phenotypes among adolescents with BD early in their course of illness. Methods: T1-weighted images were obtained from 69 Caucasian adolescents (BD=37; healthy controls (HC)=32; GPX3 AC/AA= 26; GPX3 CC=43; SOD2 AC/AA=53; SOD2 GG=15). Images were processed using FreeSurfer to obtain surface area, volume and thickness values for cortical regions of interest (ROIs; dorsolateral prefrontal cortex (dlPFC), ventromedial PFC (vmPFC), ventrolateral PFC (vlPFC), caudal anterior cingulate (cACC)), along with hippocampal volume. Results: There were significant diagnosis-by-GPX3 interaction effects on cACC thickness (F=4.02; p=0.049) and vmPFC volume (F=4.34, p=0.04). The cACC interaction was due to greater thickness in BD GPX3 A carriers vs. HC A carriers (F=4.83, p=0.03). Findings did not remain significant after correction for multiple comparisons. There were no significant findings for SOD2. Conclusion: This exploratory study yields preliminary evidence that GPX3 rs3792797 differentially impacts brain structure in regions that are relevant to BD. Further studies evaluating additional neuroimaging phenotypes, blood levels of oxidative stress markers, and neurocognition are warranted to extend upon these findings.

16. Concentrations of the fatty acid ethanolamide N-docosahexaenoylethanolamine are correlated with intrusion symptoms in post-traumatic stress disorder: a preliminary report

Erin Gaudette1,2,5, Junchao Tong, PhD1,2, Jerry Warsh, MD1-5, Tina McCluskey, MSc1,2, Shawn Rhind, MD5,7, Richard Bazinet, PhD6, Rachel F. Tyndale, PhD2,3,4, Don Richardson, MD8,9, Lin Lin5, Stephen Kish, PhD1-5, Sylvain Houle, MD PhD1-3, Matt N. Hill, PhD10, Isabelle Boileau, PhD1-


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3,5 1Research Imaging Centre and 2Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada 3Department of Psychiatry, 4Pharmacology and Toxicology and 5Institute of Medical Sciences, 6Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada 7Defense Research and Development Canada, Toronto Research Centre, Toronto, Ontario, Canada 8Parkwood Operational Stress Injury Clinic, London, Ontario, Canada 9Department of Psychiatry, University of Western Ontario, London, Ontario, Canada 10Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada Introduction: Post-traumatic stress disorder (PTSD) is conceptualized as having four distinct symptom clusters—intrusion, avoidance, negative alterations in cognitions and mood, and arousal—and an emerging body of work has implicated the endocannabinoid system (ECS) in the pathophysiology of PTSD. N-docosahexaenoylethanolamine (DHEA) is an endocannabinoid-like N-3 polyunsaturated (PUFA-3) fatty acid and a substrate of the major endocannabinoid-metabolizing enzyme Fatty Acid Amide Hydrolase (FAAH). Several FAAH inhibitors that increase DHEA as well as DHEA and PUFA-3 supplementation have been explored as potential treatments for PTSD. The aim of this study was to investigate plasma concentrations of DHEA in patients with PTSD in relation to their symptom cluster and severity. Methods: Participants with a PTSD (N = 7) and healthy controls (N = 24) completed a comprehensive psychiatric and medical interview. Participants with PTSD completed the PTSD Symptom Scale (PSS) and the PTSD Checklist (PCL). Venous blood was drawn to quantify plasma concentrations of DHEA with high-performance liquid chromatography-mass spectrometry. Results: Group differences in plasma DHEA levels between PTSD and healthy controls (N = 24) were non-significant (p=0.9). However, DHEA concentrations were significantly negatively correlated with intrusion symptoms (PCL B; R = -0.84; p = 0.03) and marginally negatively correlated with overall PTSD severity (PSS total; R = -0.61; p = 0.15; PCL R = -0.80; p = 0.06). Conclusion: Our pilot data suggest a link between DHEA and symptom severity in PTSD, specifically intrusion symptoms, such that lower levels of DHEA are associated with increased burden of intrusion symptoms (i.e., recurrent and distressing memories of the traumatic event). The finding, if confirmed in a larger sample size, may help inform therapeutic strategies already in trial, including PUFA-3 and FAAH inhibitors. Given the heterogeneity of PTSD symptomatology, further characterization of neurobiology underlying certain PTSD phenotypic sub-types may ultimately inform treatment stratification strategies.

17. Examining the relationship between oxidative stress and white matter hyperintensities in early mild vascular cognitive impairment

Mathura T. Thiyagarajah, BSc(1,2), Nathan Herrmann, MD(2,3), Damien Gallagher, MD(2,3), Sandra Black, MD(2), Joel Ramirez, PhD(2), Simon J. Graham, PhD(2,4), Pei-shan Wei, PhD(4), Paul I. Oh(5), Ana C. Andreazza, PhD(1,3), Alex Kiss, PhD(2,6), Walter Swardfager, PhD(1,2), and Krista L. Lanctôt, PhD(1,2,3) 1. Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada 2. Evaluative Clinical Sciences, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada 3. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada 4. Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada 5. Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada 6. Clinical Epidemiology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada Introduction: White matter changes are a hallmark of vascular cognitive impairment (VCI) and white matter hyperintensities (WMH), as seen on magnetic resonance imaging, have been associated with cognitive decline. Oxidative stress may lead to early white matter changes; however, the role of antioxidant mechanisms in VCI are unclear. We aim to investigate the association between the endogenous antioxidant glutathione (GSH) and WMH in mild VCI (mVCI), an early stage of VCI, and hypothesize that lower levels of GSH are correlated with greater WMH. Methods: Patients with mVCI aged 55 to 85 are recruited from a cardiac rehabilitation program.


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mVCI is defined based on neuroimaging (probable mVCI = Fazekas score = 2 OR the presence of two or more silent brain infarcts in supratentorial locations, possible mVCI = Fazekas score = 1 in the absence of silent brain infarcts) and cognitive impairment (performance = 1 standard deviation below population norms in executive function and/or verbal memory). Brain GSH will be quantified using proton magnetic resonance spectroscopy and plasma GSH will be measured using a colorimetric assay. A sample size of 55 participants is needed to assess the relationship between brain GSH levels and WMH using a linear regression. Results: To date, 15 patients are enrolled (mean ± SD; age = 69.1 ± 7.6, 80% male, 80% Caucasian). Of these, 40% of participants had possible mVCI (n = 6 with Fazekas score 1) and 60% of participants had probable mVCI (n = 1 with Fazekas score 1, n = 7 with Fazekas score 2, n = 1 with Fazekas score 3). Conclusion: White matter abnormalities of presumed vascular origin were prevalent among cardiac rehabilitation participants with cognitive decline, making them a suitable population for early intervention, in which to study the glutathione system as a novel target to mitigate disease progression.

18. Changes in Brain glutathione in patients with mild vascular cognitive impairment Jinghan Jenny Chen, MSc[1], Nathan Herrmann, MD FRCPC[2,3,10], Sandra E. Black, MD FRCPC[3,4], Joel Ramirez, PhD[3,4], Ana C. Andreazza, PhD[1], Alex Kiss, PhD[5], Paul Oh, MD FRCPC[6,7], Damien Gallagher, MD MRCPsych FRCPC[2,3], Simon Graham, PhD [8,9], Pei-Shan Wei, PhD[9], and Krista L. Lanctôt, PhD[1-4,10] 1. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada 2. Department of Psychiatry, Sunnybrook Research Institute, Toronto, ON, Canada 3. Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada 4. Department of Neurology, Sunnybrook Research Institute, Toronto, ON, Canada 5. Department of Research Design & Biostatistics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada 6. Cardiac Rehabilitation and Secondary Prevention Program-University Health Network, Toronto Rehabilitation Institute, Toronto, ON Canada 7. Department of Medicine, University of Toronto, Toronto, ON, Canada 8. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada 9. Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada 10. Department of Psychiatry, University of Toronto, Toronto, ON, Canada Introduction: Oxidative stress has been implicated in age-related neurodegeneration and dementia and may be particularly important in prodromal states such as mild vascular cognitive impairment (mVCI). Previously, we showed higher oxidative stress in patients with mVCI; however the role of antioxidant defenses in early cognitive decline is unclear. We aim to assess brain concentrations of glutathione (GSH), the primary antioxidant in the brain, in those with mVCI compared to controls. Methods: Mild VCI patients (1 standard deviation (SD) below population norms in verbal memory or executive function, age 55-85) and age- and sex-matched cognitively-healthy controls are recruited at entry into a cardiac rehabilitation program. All patients receive magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (MRS) to quantify white matter lesion burden and brain levels of GSH. Results: To date, 6 patients (mVCI n=4, control n=2) (100% male, mean±SD age 66±7 years, education 17.3±2.4 years) have been enrolled, 5 have completed MRI-MRS scans, and one is scheduled. Two mVCI patients have significant white matter lesions (Fazekas score =2), 1 mVCI patient have more than one silent brain infarcts in supratentorial locations. Of 5 MRI-MRS scans, 4 MRS passed quality control. For mVCI patients (MRI-MRS scan n=3) mean±SD GSH: anterior cingulate cortex 2.32±0.35 I.U. and occipital cortex 1.95±0.13 I.U. For control patient (MRI-MRS scan=1) anterior cingulate cortex 1.51 I.U. and occipital cortex 1.42 I.U. Conclusions/Implications: MRS measurement of brain GSH is feasible. Study findings will clarify the central antioxidant


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status in mild VCI and potentially identify the GSH antioxidant pathway as a useful therapeutic target to prevent progression to dementia.

19. Preliminary findings of a microvascular-neurostructural link in adolescents with and without bipolar disorder

Megan Mio, BSc (Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada, Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Alysha Sultan, BSc (Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada, Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Lisa Fiksenbaum, PhD (Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Sandra Black, MD, PhD, FRCPC (Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Peter Kertes, MD, FRCSC (Department of Opthalmology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Victor Yang, MD, PhD, FRCSC (Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Benjamin Goldstein, MD, PhD, FRCPC (Departments of Psychiatry and Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada, Centre for Youth Bipolar Disorder and Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada) Introduction: Neuroimaging studies have found anomalous regional brain structure among youth with bipolar disorder (BD). Thus far, it is not known whether anomalous cerebral microvasculature is associated with BD-related neurostructural differences. We examined this potential association using retinal vascular photography, a proxy of cerebral microvascular pathology. Methods: 49 adolescents (n=25 BD, n= 24 healthy controls [HC]), ages 14-19 years, underwent 3T MRI and retinal vascular photography. T1-weighted images were processed through Freesurfer to yield cortical thickness, as well as volume and surface area (SA) values for five ROIs; amygdala, hippocampus, anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (vlPFC), ventromedial prefrontal cortex (vmPFC). Retinal photographs were taken following pupil dilation with a Topcon TRC 50 DX, Type 1A camera. Retinal arterial and venular caliber were measured, and the arterio-venular ratio (AVR) was computed. Wider arteriolar and narrower venular caliber are associated with better cerebral and vascular health. Results: AVR was not significantly different between groups (t=1.69, p=0.097). In the BD group, higher arteriolar caliber was associated with larger prefrontal volume (r=0.44, p=0.03). In the HC group, narrower venular caliber was associated with greater vlPFC thickness (r=-0.57, p=0.004) and greater AVR was associated with smaller left amygdala volume (r=-0.49, p=0.01). Conclusion: These preliminary findings demonstrate associations between retinal vascular caliber and brain structure among adolescents in regions relevant to BD, and to cognition and emotion in general. Prospective studies with larger samples are warranted to evaluate the directionality of these findings and to evaluate for group-by-retinal vascular interactions.

20. A role for glycogen synthase kinase-3ß as a regulator of prefrontal cortical and hippocampal neuronal oscillations in cognition

Abdalla Albeely, Melissa Perreault Glycogen Synthase Kinase-3beta (GSK-3ß) is a constitutively active serine/threonine kinase that has been implicated in the pathology of several neuropsychiatric disorders characterized by cognitive dysfunction including schizophrenia. These disorders also exhibit dysregulation in neuronal oscillatory activity, which is known to contribute to cognitive decline. Specifically, neuronal oscillations play a key role in the synchronization of neuronal activity within and between brain regions, a process critical to brain functions such as learning, memory formation, and behaviour. A link between GSK-3ß activity and neuronal oscillatory activity has not been established. In this research, we investigated a role for GSK-3ß in the regulation of neuronal


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oscillations in the prefrontal cortex (PFC) and hippocampus (HIP), two regions integral to learning and memory processes. The study employed an AAV construct with a human mutant GSK-3ß(S9A) that was persistently active. The AAV- GSK-3ß(S9A) was injected bilaterally into PFC or HIP and the effects on neuronal oscillatory activity and cognition evaluated. Preliminary data showed that increased GSK-3ß in the HIP but not the PFC impaired spatial memory and reversal learning. Local field potential recording analysis showed that increased activation of GSK-3ß in the HIP increased the overall total spectral power in the PFC region indictive of hypersynchronous neuronal activity in that region. These preliminary results are the first to directly link GSK-3ß activity in HIP to the modulation of neuronal oscillations in the PFC, thus identifying an underlying mechanism by which GSK-3ß regulates cognitive function.

21. Causal evidence supporting the proposal that dopamine transients function as a temporal difference prediction error

Etienne JP. Maes, Melissa J Sharpe, PhD, Matthew PH Gardner, PhD, Chun Yun Chang, PhD, Geoffrey Schoenbaum, MD PhD, Mihaela D Iordanova, PhD. Center for Studies in Behavioural Neurobiology, Concordia University, Montreal, QC, Canada NIDA Intramural Research Program, Baltimore, MD, USA Correlational and causal studies have shown that reward-evoked dopamine (DA) signals in the VTA function as reward prediction errors. A critical component to this signal, according to temporal-difference learning, is the back-propagating of the error signal to the earliest possible predictor. That is, the DA response migrates back to the cue that predicts reward. It remains unknown, however, whether this cue-evoked DA response carries information regarding outcome expectation (prediction) or is a prediction-error. Here we sought to address this question using two classical behavioural paradigms, second-order conditioning and blocking. Second-order conditioning involves pairings between a neutral cue and a previously conditioned reward-predictive cue such that the neutral cue becomes predictor for the reward. In blocking, a previously trained reward-predictive cue is presented in compound with a neutral cue and this compound is followed by reward. Learning about the relationship between the neutral cue and the reward is blocked in the presence of the good predictor. By examining the effect of DA inhibition during second-order conditioning, we are able to determine whether dopamine is critical for reinforcing learning about conditioned cues. By examining the effect of DA inhibition during the reward-predicting cue in blocking, we are able to determine the role of dopamine on regulating reward prediction. Our data show that optogenetic inhibition of dopamine transients at the start of reward-predicting cues prevents acquisition of second-order conditioning without affecting blocking. That is, shunting DA neuron activity at time of the reward-predicting cue prevented that cue from reinforcing learning about itself, while shunting DA neuron activity at time of the reward-predicting cue during the second phase of blocking did not disrupt the blocking effect, suggesting that the cue-evoked DA signal does not carry information about reward prediction. These results provide causal evidence that cue-evoked dopamine signals function as temporal-difference prediction errors.

22. Effects of antipsychotics on circadian rhythm in humans: a systematic review Eunsoo Moon1, Paola Lavin Gonzalez 2, Outi Mantere 2 1 Department of Psychiatry, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea 2 Department of Psychiatry, Douglas Mental Health University Institute and McGill University, Montreal, Canada Introduction: Several studies have reported that antipsychotics might modulate circadian rhythm. Each antipsychotic agent has differential influences on circadian parameters according to pharmacological properties. The purpose of this systematic review study is to collect and integrate current evidence on the effects of antipsychotics on the circadian rhythm in humans. Methods: The following electronic databases were searched: PubMed, Cochrane Library,


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EMBASE, Ovid MEDLINE, Scopus, and CINAHL. Searching strategy included relevant combinations of circadian rhythm-related and antipsychotics-related keywords. We included randomized controlled trials, cohort study, case-control study, case series, and case reports. Two authors independently assessed the quality and the risk of bias in randomized controlled trials using Cochrane risk of bias tool and non-randomized studies using the Newcastle-Ottawa scale. In case of disagreement, we had a consensus meeting with a third review author. Results: We identified 3 randomized controlled trials among patient groups and 4 randomized cross-over studies in healthy volunteers. Especially the small number of participants and a wide variability of outcome measures limited any conclusions about efficacy of any specific diagnostic groups or with certain criteria for circadian rhythm. However, there was preliminary evidence that several antipsychotics can have an effect on diverse circadian parameters. We will summarize the findings for quality of studies and results for the specific compounds where efficacy in any circadian rhythm parameter was presented in more than 10 individuals. Discussion: The results of this systematic review support that antipsychotics seem promising as an intervention to correct disrupted circadian rhythms. However, more information to define inclusion and exclusion criteria, timing of medication as compared to individual rhythm, and outcome measures is needed before evaluating efficacy. Given the accumulating evidence about the high prevalence and unfavorable impact of disrupted circadian rhythm in several disorders, good quality intervention studies using antipsychotics are needed.

23. The heritability of subcortical structures using a twin and non-twin sibling design Nadia Blostein1,7; Sejal Patel1,4,5, PhD; Raihaan Patel1,2, M. Sc.; Stephanie Tullo1,3, M. Sc.; Eric Plitman1,6, PhD; Saashi Bedford1, M. Sc.; Gabriel A. Devenyi1,6, PhD; M. Mallar Chakravarty1,2,6, PhD. 1 Cerebral Imaging Centre, Douglas Mental Health University Institute, Verdun, Canada 2 Department of Biological and Biomedical Engineering, McGill University, Montreal, Canada 3 Integrated Program in Neuroscience, McGill University, Montreal, Canada 4Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada 5 Institute of Medical Science, University of Toronto, Toronto, Canada 6 Department of Psychiatry, McGill University, Montreal, Canada 7 Faculty of Arts & Science, McGill University, Montreal, Canada Introduction: In many imaging genetics studies, the heritability of the quantitative phenotype under study is a prerequisite for its use in future analyses. The current work examines the heritability of the thalamus, globus pallidus, and striatum, three key structures often examined in the context of neurodevelopmental and neuropsychiatric disorders. Methods: We use 3 Tesla T1-weighted structural magnetic resonance imaging (MRI) data from healthy adult twins and non-twin siblings who participated in the Human Connectome Project (n=1086 participants). Images were preprocessed using the minc-bpipe-library and subcortical structures were labeled using the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm and the CoBrA Lab subcortical atlases to obtain volume estimates. Output subcortical segmentations from MAGeT brain were manually quality controlled for accuracy, with 1008, 1007, and 1009 subjects passing for the globus pallidus, thalamus, and striatum, respectively. The OpenMx package (version 2.12.2) in R (version 3.5.1) was used to compute heritability estimates of subcortical volumes through structural equation modeling. A univariate model was used to compute the heritability of subcortical structure volume across all subjects. A bivariate model was used to compute the shared heritability between total brain volume and subcortical volume. Results: Univariate model results showed significant genetic effects (p < 0.001) and yielded heritability estimates ranging from 74% to 88%. The Pearson correlation between total brain volume and subcortical structure volume ranged from 0.71 to 0.84. Bivariate model results showed significant genetic effects (p < 0.001) and yielded heritability estimates ranging from 75% to 88%.


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The genetic correlation between total brain volume and subcortical structure volume ranged from 0.76 to 0.86. Conclusions: These results suggest that the phenotypic correlation between subcortical volumes is largely due to genetic effects. The current findings may lead to a better understanding of genetic risk factors in illnesses with subcortical pathophysiology.

24. The interaction between circadian disruption and a neurodevelopmental risk factor for schizophrenia

Tara Delorme1,2, BSc, Lalit Srivastava2,3 PhD and Nicolas Cermakian2,3 PhD. 1Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada. 2Douglas Mental Health University Institute, Montréal, Québec, Canada. 3Department of Psychiatry, McGill University, Montréal, Québec, Canada Introduction: It is widely accepted that numerous genetic and environmental insults combine to increase one’s susceptibility to developing schizophrenia. How these risk factors interact to trigger disease onset and how they influence disease severity is poorly understood. Our main hypothesis is that circadian rhythm disruption (CRD) contributes to schizophrenia. Methods: We used a neurodevelopmental mouse model of schizophrenia based on prenatal infection (mIA). We first hypothesized that the combination of mIA and CRD would uncover or exacerbate behavioural deficits. MIA-exposed mice and controls were subjected a typical light/dark cycle (12:12LD) for baseline measurements, then to constant light exposure (LL; known to disrupt circadian rhythms), then back to 12:12LD for a light ‘rescue’. We secondly hypothesized that mIA-exposed mice had impaired diurnal and circadian rhythms, akin patients with schizophrenia. Mice were placed in running wheels and exposed to different lighting challenges. Results: When measuring locomotion, mIA males showed more horizontal activity (p=.0165) and greater distance traveled (p=.0095) than controls. In the elevated plus maze (EPM), only after LL exposure did mIA males show 2 phenotypes, where most mice displayed high anxiety-like behaviour. This was not seen after the light ‘rescue’. MIA males also showed more distance traveled in EPM than controls (p=.0344). In a social interaction test, mIA males had less preference for a stranger mouse than controls (p=.0137), with a larger effect after LL treatment (p=.0068). In prepulse inhibition, male and female mice show sensory-motor deficits (p<.05). In running wheels under a 12:12LD, mIA-exposed offspring were more active during the light (p=.006), had higher interdaily stability (p=.011) and a shorter alpha (p=.005) than controls. In constant dark and light, mIA-exposed offspring had more subjective day running (p=.038 and p=0.014 respectively). Conclusion: The results of this project will aid in finding novel and efficient therapeutic targets for those suffering from schizophrenia.

25. Contribution of D1- and D2-mediated signalling to the expression of antipsychotic-evoked dopamine supersensitivity

Alice Servonnet, Alice Gravel-Chouinard, Florence Allain, Giovanni Hernandez, Daniel Lévesque and Anne-Noël Samaha Introduction: Antipsychotic drugs attenuate psychosis symptoms by decreasing dopamine signalling via dopamine D2 receptors. Chronically decreasing dopamine signalling can produce sensitization to dopamine receptor stimulation, and this can impair treatment efficacy and worsen psychosis. In animals, dopamine supersensitivity is indicated by an exaggerated behavioral response to dopamine agonists, such as amphetamine. Here, we investigated the neurobiological mechanisms underlying the expression of antipsychotic-evoked dopamine supersensitivity in rats. In Experiment 1, we measured striatal levels of the proteins GSK3ß and AKT that are, respectively, activated and inhibited by D2 receptor activation. In Experiment 2, we investigated whether D1 or D2 transmission is necessary for the expression of antipsychotic-evoked dopamine


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supersensitivity. Methods: We treated rats with the antipsychotic haloperidol for 16 days. We then assessed amphetamine-induced locomotion in both groups. In Experiment 1, brains were extracted 1 hour after amphetamine injection and GSK3ß and AKT levels were measured in the striatum. In Experiment 2, we assessed the effects of a D1 (SCH39166; 0.03 and 0.1 mg/kg) or D2 (sulpiride; 25 or 80 mg/kg) receptor antagonist on amphetamine-induced locomotion. Results: In both experiments, amphetamine-induced locomotion was potentiated in haloperidol-treated rats, indicating dopamine supersensitivity. In Experiment 1, haloperidol-treated rats also had enhanced amphetamine-induced increases in GSK3ß levels (nucleus accumbens and dorsolateral caudate-putamen) and decreases in AKT levels (nucleus accumbens). This suggests that antipsychotic-induced dopamine supersensitivity involves amplified D2-mediated signalling. However, in Experiment 2, sulpiride decreased amphetamine-induced locomotion only in controls. SCH39166 decreased amphetamine-evoked locomotion similarly in controls and antipsychotic-treated rats. Conclusions: D1- but not D2-mediated signalling could be required for the expression of antipsychotic-evoked dopamine supersensitivity. Our findings also support the idea that dopamine supersensitivity is linked to tolerance to the anti-dopaminergic effects of D2 receptor antagonists/antipsychotics. Thus, our animal model will be useful to uncover strategies to attenuate antipsychotic-evoked dopamine supersensitivity.

26. The effects of transcranial direct current stimulation and paroxetine on depressive-like behaviours in adolescent rats

Shannon Waye, BS, Francis R. Bambico, PhD Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada Introduction: Adolescent depression is a complex condition without a clear solution, as current treatments have been shown to produce paradoxical effects that result in the worsening of depressive symptoms. Therefore, we tested if a non-invasive brain stimulation technique known as transcranial direct current stimulation (tDCS) could be used as an adjunct treatment to antidepressant drug therapy to counteract these negative effects. Methods: We induced a depressive-like phenotype in adolescent Sprague-Dawley rats using olfactory bulbectomy (OBX), a rodent model of depression that results in behavioural and neurochemical changes that are reversed by antidepressant treatment. We examined if two weeks of tDCS treatment (50 µA, 15 minute sessions) was sufficient to produce reductions in OBX-induced depressive-like behavioural symptoms, including hyperlocomotion in an open field chamber and deceased sucrose consumption, and if this effect was achievable with tDCS alone or with adjunct Paroxetine treatment (20mg/ml). Results: We found that tDCS, but not paroxetine, was able to successfully reverse the OBX-induced hyperlocomotion in the open field test, F(1,28) = 4.397, p = .045. Additionally, acute administration of Paroxetine caused a significant reduction in sucrose preference, F(1,47) = 7.050, p = .011, an effect that was completely blocked by concurrent tDCS stimulation. Sucrose preference was normalized after chronic treatment of Paroxetine, with no additional benefit of concurrent tDCS. Conclusion: These findings support the idea that SSRI treatment results in the worsening of depressive symptoms, particularly at the start of treatment. They also suggest that tDCS is an effective treatment for adolescent depression and can be used to treat the disorder in place of, or in addition to, SSRI administration.

27. Delusions in first episode psychosis Ann-Catherine Lemonde, MSc Candidate, Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, CA Patricia Boksa, PhD, Department of


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Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, CA Jai Shah, MD FRCPC, Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, CA Introduction: During a psychotic episode, patients frequently suffer from false but fixed beliefs known as delusions. This proposed poster presentation reports on delusions in the early phases of psychosis. Despite the abundant literature investigating the simple presence or absence of these beliefs, there exists little detailed knowledge regarding their actual content and severity at the onset of illness. Methods: Data was systematically collected, from a catchment-based help-seeking sample of 671 clients entering an early intervention service for first episode psychosis (FEP) in Montreal. The average severity and frequency of each delusional theme at baseline was reported using the Scale for Assessment of Positive Symptoms. Delusion severity, both globally and per theme, was examined across a number of sociodemographic and clinical variables. Statistical analyses included Mann-Whitney U tests and Spearman rank-order correlations. Results: Delusions were present in the vast majority of individuals experiencing onset of a FEP (93%), with persecutory as the most common delusion theme (77.3%) and jealousy as the least common (3.1%). Eighty percent of clients experienced more than one delusional theme. Globally, delusion severity was positively associated with two symptoms: bizarre behavior and avolition/apathy. On average, those above the age of 18 had more severe delusions than younger clients. A higher severity of delusions was found for those who abuse substances. Conclusion: Persecutory delusions were the most common delusion theme in this large FEP sample. However, the majority of subjects present with multiple delusion themes. Our findings suggest that certain social and clinical factors are linked both with the global rating and theme-specific ratings for delusion severity. Future research should investigate the course of delusion themes over time, and perhaps focus on specific themes to untangle their role within individual psychotic experiences.

28. Distinct neuronal ensembles within the central nucleus of the amygdala regulate extinction learning

Belinda P.P. Lay, PhD. Center for Studies in Behavioural Neurobiology, Department of Psychology, Concordia University, Montreal, QC, Canada Mihaela D. Iordanova, PhD. Center for Studies in Behavioural Neurobiology, Department of Psychology, Concordia University, Montreal, QC, Canada Introduction: Correlational data from histochemical and physiological studies suggest that the central nucleus of the amygdala (CeA) is involved in learning when expected events are omitted. Attempts at delineating the causal contribution of CeA neurons to this learning have targeted the entire nucleus indiscriminately, disrupting the function of neurons. Recent research using selective approaches have uncovered that not all neurons within a brain area are recruited during learning. Rather, a specific neuronal ensemble supports learning with distinct subsets of neurons likely having different functional roles. We sought to determine the functional role of CeA neurons that have been explicitly activated by the omission of an expected reward in updating reward expectations during extinction. We predicted that inactivating these activated neuronal ensembles using the Daun02 inactivation procedure will disrupt the reduction in behavioural responding. Methods: Male c-fos-lacZ transgenic rats were trained to expect the delivery of a food reward upon the presentation of an auditory cue. Subsequently, rats received non-reinforced exposure to the reward-associated cue to generate conditions of reward omission, that is extinction, and examine the effect of this on learning. Cell inactivation with Daun02 took place ninety minutes following the start of the non-reinforced session, presumably when the neurons that detected the reward omission were activated and the corresponding c-fos levels were at peak. Results: Inactivating activated CeA neurons following extinction learning led to disruption in


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behaviour at test indicative of impaired retrieval of the extinction memory compared to rats that received a vehicle infusion, which left those neurons intact. Additional data show that further extinction learning was retarded in the absence of the neuronal ensemble in the CeA. Moreover, this disruption in behaviour was not due to drug diffusion into the basolateral amygdala. Conclusion: There are distinct neuronal ensembles in the CeA that regulate extinction learning and re-learning. 29. Mapping alpha-synuclein-induced brain pathology in a mouse model of

Parkinson’s disease 1) Stephanie Tullo, MSc Brain Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada 2) Daniel Gallino, MSc Brain Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada 3) Esther del Cid-Pellitero, PhD Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada 4) Edward A. Fon, MD, FRCP(C) Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada 5) M. Mallar Chakravarty, PhD Brain Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada Department of Biological & Biomedical Engineering, McGill University, Montreal, Quebec, Canada Department of Psychiatry, McGill University, Montreal, Quebec, Canada Introduction: While the mechanism underlying Parkinson’s Disease (PD) pathology has not yet been elucidated, recent evidence suggests alpha-synuclein (aSyn) may propagate in a prion-like manner, mediating the spread of pathology and contributing to PD progression. Using a transsynaptic aSyn mouse model of PD, we examined magnetic resonance imaging (MRI)-derived measures to link aSyn aggregates to brain atrophy. Methods: Intracerebral inoculation of M83 aSynA53T transgenic mice (n=8 mice/group; 4 males and 4 females) was performed where one group received an injection of the pathological form of aSyn (preformed fibrils; PFF) in the right dorsal neostriatum, in order to accelerate the formation of intracellular PD pathology. At 90 days post-injection (the onset of symaptology), the mice were sacrificed and imaged ex-vivo (Bruker 7T; T1-weighted images; 70 µm3 voxels). Whole structure volume differences between the PFF and control (PBS; Phosphate-buffered saline) group were examined using atlas-based segmentation, performed using the MAGeT-Brain algorithm. A general linear model was used to examine brain structure volume differences between the groups, modelling sex as a covariate. False discovery rate (FDR) was used to correct for multiple comparisons. Results: At FDR 15%, smaller volumes for the PFF injected mice were observed for the right thalamus and regions of the frontal cortex (left medial orbital cortex, right primary motor cortex, and left primary somatosensory cortex, hindlimb region) (t>3.83). Conclusion: The inoculation of aSyn PFF in the striatum showed widespread effects on brain morphology, particularly in regions that project to, or receive input from the injection site. These results are in accordance with immunohistochemistry studies in which showed prominent aSyn pathology in the neurons of these same structures following striatal PFF innoculation. Whole brain longitudinal examination of aSyn spreading, brain structure, and behavioural symptom progression are currently being performed to characterize a signature of network spreading and disease progression.

30. Behavioral consequences of Bmal1 deletion within the mouse striatum Konrad Schottner, PhD; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Margo Button; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Jory Goldsmith; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Pavel Solis; Center for Studies in


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Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Nuria de Zavalia, PhD; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Shimon Amir, PhD; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Quebec, Canada Circadian clocks generate daily oscillations of biological functions, ranging from molecular processes to rhythms in physiology and behavior. Proper function of this internal time-keeping mechanism is vital to provide an intrinsic temporal order of biological functions within the organism and to time physiological and behavioral processes appropriately, with respect to the 24-h environment. Beside the master circadian pacemaker, which is the suprachiasmatic nucleus located in the hypothalamus that maintains and synchronizes the timing of biological functions in accordance to the environment, peripheral clocks reside in other brain areas to set region-specific rhythmic functions. The circadian clock in medium spiny neurons (MSNs) of the striatum is of great interest given the role of this brain region in the expression of certain neuropsychiatric disorders. To investigate the significance of a functional circadian clock in striatal MSNs, conditional knockouts of the core circadian clock gene Bmal1 were generated and confirmed by mRNA and protein expression analysis. Subsequently, mice were tested to assess the impact of the Bmal1 knockout in striatal MSNs on behavior with focus on circadian as well as mood- and anxiety-related phenotypes. Whereas daily locomotor activity rhythms are similar in Bmal1 knockouts compared to control mice, it is shown that Bmal1 knockout animals display higher levels of locomotor activity, tend to spend less time in the center of an open field arena and display increased thigmotactic behavior in an open field test compared to control mice. Shorter immobility time is observed in Bmal1 knockout mice compared to control counterparts in a tail suspension test. The results of the current study indicate that loss of the circadian clock gene Bmal1 in the striatum appears to be involved in the incidence of anxiety-related conditions and hyperactivity in novel environments, however, further studies need to be conducted in order to draw final conclusions. 31. Effect of neonatal ablation of ventral hippocampus excitatory neurons on social and

cognitive functions in adult mice A.T. Joseph, S. K. Bhardwaj and L. K. Srivastava Ventral hippocampus (VH) modulates behaviors such as executive control, emotions and goal directed behaviors by connectivity to various cortical and limbic regions (prefrontal cortex (PFC), nucleus accumbens and amygdala). Developmental behavioral disorders are hypothesized to arise from a disruption in VH-PFC/limbic connectivity. A model to test this hypothesis, the neonatal ventral hippocampus lesion (NVHL) model in rats, has revealed that lesion of the VH in pups leads to adult schizophrenia-like behavioral deficit (hyperlocomotion, social memory deficit and cognitive deficits). Since NVHL model uses the indiscriminate excitotoxicity of the ibotenic acid to lesion the VH, the specific role of the neonatal VH neuronal populations on adult behavior cannot be inferred from this model. Thus, we reasoned that neonatal ablation of the VH excitatory neurons may be responsible for adult behavioral deficits. In order to test this hypothesis, an adeno-associated viral 8 (AAV8) vector carrying diptheria toxin A (dTA) was microinfused bilaterally in the VH of C57Bl6/J Cam-cre mice (P12). After 21 days of microinjection, we confirmed the virus expression, injection site and ablation of the excitatory neurons by performing immunohistochemistry using mCherry, CaMKII and c-Fos antibodies followed by cell counting. Adult mice were used to assess behaviors. Our data showed no significant change in spontaneous locomotor activity in the dTA virus group as compared to the control virus group. Male dTA virus group exhibited a deficit in social memory and spatial memory retention as compared to the control virus group as assessed by social novelty test and Barnes maze respectively. This shows that specific neonatal ablation of the VH excitatory neurons can lead to some aspects of deficits in social and cognitive functions. Also


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suggesting that neonatal ablation of other neuronal or non-neuronal cells in the VH could be involved in other aspects of adult cognitive behaviors.

32. Delta-9-tetrahydrocannabinol in neuropathic pain and comorbid insomnia Martha López-Canul1, Alexandra Teggin2, Antonio Farina3 , Maria-Luisa Vigano4, Luca Posa5, Danilo De Gregorio6, Shelly Yin7, Gabriella Gobbi8. 1 Martha López-Canul, PhD, Department of Psychiatry, McGill University, Montreal, QC, Canada, [email protected] 2 Alexandra Teggin, Department of Psychiatry, McGill University, Montreal, QC, Canada. [email protected] 3 Antonio Farina, Department of Psychiatry, McGill University, Montreal, QC, Canada. [email protected] 4 Maria-Luisa Vigano, Department of Psychiatry, Degrees McGill University, Montreal, QC, Canada. [email protected]. 5 Luca Posa, Department of Psychiatry, McGill University, Montreal, QC, Canada. [email protected] 6 Danilo de Gregorio, PhD, Department of Psychiatry, McGill University, Montreal, QC. Canada. [email protected] 7 Shelly Yin, Department of Psychiatry, McGill University, Montreal, QC, Canada. [email protected]. 8 Gabriella Gobbi, MD PhD, Department of Psychiatry, McGill University, Montreal, QC, Canada. [email protected] Introduction/Aim: Neuropathic pain (NP) is a major health problem which results in high suffering, decreased productivity and exorbitant health care costs. An estimated 50% to 88% of patients with NP develop sleep disturbances (Finan et al., 2013). At present, only a restricted number of effective drugs are clinically available for NP associated to insomnia. The delta-9-tetrahydrocannabinol (THC) may offer a novel approach to the chronic pain management and insomnia, but its efficacy in these two condition is not yet fully understood. Methods: We induced NP (spared nerve injury) in Wistar rats, 14 days later were treated with vehicle (VEH; 5%Tween 80, 5% PEG and saline) or THC (1, 1.5, 2, 2.5 and 5 mg.kg, i.p.) to assess mechanical allodynia. Then, rats with NP (spared nerve injury) were implanted with six stainless-steel wire electrodes in the skull and EEG/EMG was recorded for a period of 6 h (from 6 AM to 12 PM). Results: THC (2.5 and 5 mg/kg) decreased mechanical allodynia in rats with NP (p<0.001) vs VEH, 1h. after administration in a dose dependent-manner. This effect lasted about 3.5 hours. EEG/EMG analysis showed that rats with NP had a reduced time in non-rapid eyes movement (NREM) sleep (-35%, p<0.05) and increased wakefulness (+39.6%, p<0.05) compared to naive rats. THC (5 mg/kg) was able to restore the normal sleep-wake cycle in NP rats. Discussion/ Conclusions: The findings suggest that THC has a moderate analgesic effect and good hypnotic effect in a NP paradigm, similar to clinical outcomes reported in humans.

33. The effects of continuous, low dose amphetamine treatment on behavioural features of cocaine addiction in female rats

Ndeye Aissatou Ndiaye (1), Florence Allain (2), Anne-Noël Samaha (2,3) 1- Department of neuroscience, Faculty of Medicine, Université de Montréal, 2- Department of pharmacology and physiology, Faculty of Medicine, Université de Montréal, 3- Groupe de recherche sur le système nerveux central, Faculty of Medicine, Université de Montréal Aims: Currently, there are no approved medications to treat cocaine addiction. Continuous, low-dose d-amphetamine treatment is considered the most promising pharmacological strategy to reduce cocaine use. In both rats and human cocaine users, low-dose amphetamine acts as an agonist substitution therapy to reduce cocaine taking and seeking. However, to this day, there are no published studies on this issue in female animals, even though in humans, cocaine addiction afflicts both women and men, and women can be more vulnerable to addiction-relevant effects of cocaine. Here, we assessed in female rats the effects of continuous, low-dose amphetamine treatment on behavioural features of cocaine addiction.


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Methods: Female rats will first receive 14 cocaine self-administration sessions (1/day) during which we will measure drug intake. We will then establish baseline levels of responding for cocaine under a progressive ratio schedule (measure of motivation to take cocaine). Next, all rats will be allowed to self-administer cocaine during 14 more sessions. During these sessions, two-thirds of the rats will receive continuous d-amphetamine treatment (5 or 2.5 mg/kg/day, via subcutaneous osmotic minipump). The remaining third will remain d-amphetamine-free and serve as control group. Finally, we will re-assess the motivation to take cocaine as well as cocaine-induced relapse behaviour. Thus, we will be able to compare cocaine-taking and -seeking behaviours before and after d-amphetamine treatment. Results: If d-amphetamine has similar anti-cocaine addiction effects in females as it does in males, then after d-amphetamine treatment, our female rats here should show decreased levels of both motivation to take the drug and cocaine-seeking behaviour after abstinence. Conclusion: To our knowledge, these results will provide the first account of the effects of continuous, low-dose d-amphetamine treatment on addiction-relevant behavioural features in female animals. This will inform future work on the potential anti-addiction effects of d-amphetamine treatment in females with cocaine addiction.

34. Assessing the role of serotonin-2B receptor antagonism in the antidepressant response: an in-vivo electrophysiological study in the rat brain

Rami Hamati, BSc 1,2, Mostafa El Mansari, PhD 2, Pierre Blier, MD/PhD 1,2 1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada 2 Mood Disorders Research Unit, The Royal’s Institute of Mental Health Research, Ottawa, ON, Canada Introduction: Using serotonin (5-HT)-2B receptor (5-HT2BR) KO mice, previous research has demonstrated that 5-HT2BRs contribute to the antidepressant-like response. Several dopamine-serotonin partial agonists (i.e. aripiprazole; previously known as atypical antipsychotics) that exhibit high affinity antagonism at the 5-HT2BR have been successfully used in combination with selective-serotonin reuptake inhibitors (SSRIs) in difficult to treat major depressive disorder. However, the exact contribution of the antagonistic action of aripiprazole on 5-HT2BRs in the context of adjunct therapy is not known. Methods: In-vivo electrophysiological recordings of ventral tegmental area (VTA) dopamine (DA) neurons and medial prefrontal cortical (mPFC) pyramidal neurons were conducted in anaesthetized Sprague-Dawley rats. Results: Although mean firing rate of DA neurons was not altered, acute administration of the 5-HT2BR agonist BW723c86 (6 mg/kg, i.v.) decreased their bursting activity (N=7, p=.038), which was abolished by pre-administration of the selective 5-HT2BR antagonist RS127445 (2 mg/kg, s.c). After two days, an SSRI-induced (escitalopram 10 mg/kg/day via osmotic minipump) decrease in DA mean firing rate (N=3, p<.001) was rescued by co-administration of the selective 5-HT2BR antagonist LY266097 (0.6 mg/kg/day, i.p.). Aripiprazole (2 mg/kg/day, s.c.) administered alone or in combination with escitalopram for 14 days increased pyramidal neuron mean firing rate and bursting activity (N=5, p<.05 and p<.01 respectively). Although escitalopram had no effect alone, LY266097 alone or the addition of LY266097 for the last three days of a 14-day escitalopram treatment resulted in an increase of pyramidal neuron activity similar to aripiprazole addition (N=6, p<.001 and N=7, p<.01 respectively). Conclusions: 5-HT2BR blockade rescues an SSRI-mediated decrease in VTA-DA mean firing rate. The increase in mPFC-pyramidal neuron activity mediated by aripiprazole alone and in combination with escitalopram may be, at least partly, attributed to 5-HT2BRs expressed in this region. Altogether, these results strengthen the view that 5-HT2BRs contribute to the therapeutic effect of aripiprazole.

35. Plasma N-acylethanolamines and endocannabinoids concentrations in chronic frequent cannabis users during early abstinence


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Nadia Boachie1,5, Erin Gaudette1,5, Richard Bazinet1-3,5, Lin Lin1,5, Esmaeil Mansouri1,5, Marilyn Huestis6, Junchao Tong1,2, Stephen Kish1-3,5, Tony George1-3,5, Isabelle Boileau1-3,5. 1Research Imaging Centre and 2Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health 3Department of Psychiatry, 4Department of Pharmacology and Toxicology and 5Institute of Medical Science, University of Toronto 6Lambert Center for the Study of Medicinal Cannabis and Health, Thomas Jefferson University, Philadelphia, PA Purpose: Frequent cannabis use is prevalent and associated with health conditions including acute and chronic psychiatric illness. N-acylethanolamines (NAE) and endocannabinoids (EC) are lipid signalling molecules with roles in metabolic, inflammatory and mental health conditions and have been linked with drug-taking behaviors. There is limited data on EC and NAE levels in individuals with addictions. The aim of the study was to determine plasma EC and NAE concentrations in individuals with cannabis use disorder (CUD) during early abstinence compared to healthy controls. Methods: Fifty-four controls and 11 frequent cannabis users (overnight abstinent) provided plasma for measurements by high-performance liquid chromatography-mass spectrometry of ECs and other NAE: anandamide (AEA), 2-Arachidonoylglycerol (2-AG), N-Docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA). Clinical scales were administered and cannabis metabolites were measured in blood and urine. Results: Concentrations of EC’s AEA DHEA and OEA were significantly elevated in CUD (25%, p =0.001; 39%, p =0.031; 40%, p =0.016 respectively). 2-AG although non-significant were also elevated (55%, p = 0.130). DHEA concentrations were inversely associated with craving, as per Marijuana Craving Questionnaire (r = -0.86; p=0.001). Conclusion/Implications: This is the first study reporting elevated plasma concentrations of ECs and NAEs in humans with CUD during early abstinence. Our findings may suggest an adaptive response to chronic cannabis exposure which could mask withdrawal symptoms during early abstinence. Studies examining ECs and NAEs during prolonged abstinence are needed.


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Poster Session 2 – Friday June 14, 2019 17:15 – 19:15 – Restaurant, Basement Level

1. Examination of hippocampal subfield volume in treatment-resistant depression Patricia Burhunduli, BSc 1,2, Adel Farah, MD 1, Katie L. Vandeloo, BSc 1, Pierre Blier, MD, PhD 1,2,3, Jennifer L. Phillips, PhD 1,3. 1. Mood Disorders Research Unit, The Royal’s Institute of Mental Health Research, Ottawa, ON, Canada. 2. Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada. 3. Department of Psychiatry, University of Ottawa, ON, Canada Introduction: Reduced hippocampal volume is one of the most widely replicated structural neuroimaging findings in major depressive disorder (MDD). Despite known associations between the hippocampus and depression, little is known about the unique contribution of specific hippocampal subfields to the volumetric changes associated with depression. This study explored the relationship between depression severity and hippocampal subfield volumes in a clinically well-defined sample of patients with treatment-resistant MDD. Methods: Hippocampal total and subfield volumes were assessed using magnetic resonance imaging (MRI) in 20 participants with treatment-resistant MDD. T1-weighted structural images were acquired at 3T using a multi-echo magnetization-prepared rapid gradient echo (MPRAGE) protocol. Cortical reconstruction and segmentation were performed using FreeSurfer-6.0.0. Severity of depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale. Results: Controlling for age, sex and total intracranial volume, Pearson partial correlations revealed negative associations between depression severity and total left hippocampal volume (r=-0.60; p=0.011) and left subfield regions CA1 (r=-0.59; p=0.013), CA3 (r=-0.57; p=0.018), CA4 (r=-0.49; p=0.045), molecular layer (r=-0.62; p=0.008) and hippocampal-amygdala transitional area (HATA) (r=-0.58, p=0.014). There was no significant association between depression severity and volume of the remaining hippocampal subfields or total hippocampal volume in the right hemisphere. Conclusion: The hippocampus is a highly heterogeneous structure and distinct subfields may be differentially involved in MDD. Preliminary results in our small sample suggest that specific hippocampal subfield volumetric changes are differentially associated with depression severity. Research focusing on hippocampal subfields may provide insight on the potential contributions of hippocampal volume loss to continuing depressive symptoms.

2. Intestinal permeability correlates with behavioural severity in very young children with ASD

Grace Teskey1,5, Evdokia Anagnostou2,3, Deepali Mankad2, Sharon Smile2, Wendy Roberts4, Jessica Brian2,3, Dawn ME. Bowdish1,5, Jane A. Foster6 1Department of Pathology and Molecular Medicine, McMaster University, Hamilton ON 2 Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital 3 Department of Pediatrics, University of Toronto, Toronto ON 4 Sick Kids, University of Toronto, Toronto, ON 5 McMaster Immunology Research Centre, McMaster University, Hamilton ON 6Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton ON Introduction: Systemic inflammation is known to alter behaviour, and it has been reported that individuals with autism spectrum disorder (ASD) have higher levels of circulating pro-inflammatory cytokines. Individuals with ASD also more frequently report gastrointestinal symptoms and intestinal barrier dysfunction. A possible consequence of barrier dysfunction is the translocation of bacteria and bacterial products into the circulation, which could lead to an inflammatory response including the production of acute phase proteins and pro-inflammatory cytokines. We hypothesize


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that intestinal barrier dysfunction and systemic inflammation may exacerbate behaviours characteristic of ASD. Methods: The acute phase proteins a-2-macroglobulin, C-reactive protein, haptoglobin, serum amyloid P, serum amyloid A, ferritin and tissue plasminogen activator, as well as markers of intestinal permeability (intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide) were quantitated in the plasma of very young children with ASD. Behaviour severity was measured using the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and the Vineland Adaptive Behaviour Scale (VABS). Results: An increase in circulating levels of I-FABP correlated with more severe deficits in communication, communication + social interaction as well as maladaptive behaviour using Spearman rank correlation. The acute phase protein haptoglobin was associated with more severe social interaction and communication + social interaction. Conclusions: I-FABP, a marker of intestinal epithelial damage, was associated with more severe behavioural phenotypes in very young children with ASD. In addition, the acute phase protein, haptoglobin, was associated with more severe behaviour.

3. Molecular adaptations of the blood-brain barrier promoting depression and stress resilience

Katarzyna Anna Dudek 1, Laurence Dion-Albert 1, Manon Lebel1, Katherine LeClair2, Ellen Tuck1,3, Carmen Ferrer Perez4, Sam A. Golden5, Naguib Mechawar6, Scott J. Russo2, Caroline Menard1 1Université Laval & CERVO Brain Research Center, Quebec City (Canada), 2Icahn School of Medicine at Mount Sinai & Friedman Brain Institute, New York (USA), 3Trinity College Dublin, Dublin (Ireland), 4University of Valencia, Valencia (Spain), 5University of Washington, Seattle (USA), 6McGill University & Douglas Mental Health University Institute, Montreal (Canada) Abstract: Major depressive disorder (MDD) is the leading cause of disability worldwide and will affect20% of individuals. MDD is a recurrent condition and only 30% of patients remit completely. This low efficacy level suggests that conventional treatments do not address causal biological factors. Clinical studies report higher prevalence of MDD in patients suffering from vascular diseases, indicating that increased inflammation and vascular dysfunction may contribute to depression pathogenesis. We showed that chronic stress, depression’s main environmental risk factor, induces blood-brain barrier (BBB) leakage in the nucleus accumbens (NAc) of mice, promoting depression-like behaviors. Here, we characterized molecular adaptations underlying stress susceptibility (SS) vs resilience (RES) in the NAc endothelial cells of C57Bl6 mice. Mice were subjected to 10-day chronic social defeat stress followed by social interaction test 24h later to determine behavioral phenotype. Then, NAc punches were collected and cell-specific magnetic activated cell sorting was performed followed by transcriptome-wide gene-level expression analyses. We observed specific gene expression patterns in endothelial cells of the NAc of SS vs RES. Importantly, such changes were also present in RES vs control mice indicating that BBB molecular adaptations are necessary to maintain its integrity under chronic stress conditions. We confirmed changes in BBB-related gene expression in postmortem NAc samples of MDD patients supporting a role for the vasculature in depression and possibly novel therapeutic strategies. Funding: Brain & Behavior Research Foundation (NARSAD), Canada First Research Excellence Fund (Sentinel North Initiative), Fonds Recherche du Québec – Santé, CERVO Brain Research Center, Fonds Hélène-Hallé & Faculty of Medicine (Université Laval)

4. Effects of intermittent-access versus continuous-access nicotine self-administration in rats

Eric Borduas, Florence Allain, Hajer Algallal, & Anne-Noël Samaha. Université de Montréal, Medical Faculty, Department of Neuroscience, Laboratory of Dr. Anne-Noël Samaha


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Introduction: Cigarette smokers consume nicotine and the other tobacco products found in cigarettes intermittently throughout each day. Yet, procedures to study nicotine effects in laboratory animals involve continuous nicotine access during each self-administration session. Here, we compared in rats the effects of intermittent versus continuous nicotine self-administration on behavioural features relevant to drug addiction. Methods: Male rats self-administered nicotine (i.e., 0.015 or 0.03 mg/kg/infusion) during 14 sessions (7 h/session). One group had continuous nicotine access during each session (Long Access, or LgA). The other group had intermittent access (IntA; 12 minutes of access to nicotine per hour). This produced 4 groups; LgA-0.015, LgA-0.03, IntA-0.015 and IntA-0.03. We assessed group differences in nicotine intake, responding for nicotine under a progressive ratio schedule of reinforcement (a measure of incentive motivation for drug). After nicotine withdrawal, we also measured the susceptibility to cue- (withdrawal days 15-30) and nicotine-primed (0.075–0.15–3 mg/kg, subcutaneous; withdrawal days 30-38) reinstatement of nicotine-seeking behaviour (measures of relapse). Results: LgA-0.03 rats consumed the most nicotine across the 14 self-administration sessions. However, in spite of taking much less nicotine than LgA groups, IntA groups showed similar levels of responding for nicotine under a progressive ratio schedule. After nicotine withdrawal, all groups also showed equivalent levels of cue- and nicotine- induced reinstatement behaviour. Conclusion: IntA nicotine self-administration achieves much less drug intake than LgA self-administration, yet the two procedures are equally effective in producing behavioural signs relevant to tobacco addiction. IntA nicotine self-administration also better models the intermittency of cigarette smoking in humans. Thus, our findings have important implications for preclinical studies investigating the behavioural, psychological and neurobiological processes involved in addiction to tobacco.

5. Investigating brain astrocyte status in alcohol use disorder with the monoamine oxidase B positron emission tomography tracer [C-11]SL25.1188

Jennifer Truong HBSc1,5, Laura M. Best HBSc1,5, Tina McCluskey M.Sc1-2, Junchao Tong Ph.D1-3, Pablo Rusjan Ph.D1-3,5, Jeffrey Meyer MD Ph.D 1-5, Bernard Le Foll MD Ph.D1-5, Christian Hendershot Ph.D2-3, Jerry Warsh MD Ph.D1-5, Sylvain Houle MD Ph.D1-3, Stephen Kish Ph.D1-5, Isabelle Boileau Ph.D1-3,5 1Research Imaging Centre and 2Campbell Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada 3Department of Psychiatry, 4Pharmacology and Toxicology and 5Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada Introduction: Alcohol use disorder (AUD) is associated with substantial consequences to Canadian society resulting in an economic burden of $14.6 billion annually. Despite ongoing clinical efforts, the relapse rates in AUD are still too high. Astrocytes are proposed as an innovative therapeutic target involved in the pathophysiology of AUD and in addictive behaviour. Our objective is to measure brain binding of the Monoamine Oxidase B (MAOB) positron emission tomography (PET) radiotracer, [C-11]SL25.1188, a putative marker of astroglia levels. Based on post-mortem human brain findings, we hypothesize that [C-11]SL25.1188 binding will be lower in the hippocampus and prefrontal cortex of patients with AUD. Methods: PET images of [C-11]SL25.1188 binding with arterial blood sampling were acquired in treatment-seeking participants with a DSM-IV diagnosis of AUD during the early abstinence phase (the week after the last alcohol use). [C-11]SL25.1188 total distribution volume (VT) in hippocampus and prefrontal cortex were obtained using a two-tissue compartment model. Results: AUD participants (n=6, M/F=5/1, 51.5±6.69 years old, Mean ± SD) and controls (n=15, M/F=9/6, 43.1±11.1 years old) have completed the study. An ANCOVA (age as a co-variate) revealed that while [C-11]SL25.1188 VT was modestly lower in both hippocampus (9%, p=0.38) and prefrontal


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cortex (4%, p=0.74) of AUD subjects compared with controls, the differences in binding were not statistically significant (F(1,18)=0.40, p=0.53). Conclusion: In our early data set, we found no evidence suggesting abnormal brain astroglia status in AUD as inferred from MAOB/[C-11]SL25.1188 binding. However, continuous recruitment of AUD participants in our ongoing study may well provide findings that will modify this tentative conclusion. This will be the first in vivo study looking at astrocyte status in alcohol users. Data are limited on status of brain astrocytes in AUD, and this imaging study may give further insight into the behaviour of this potential therapeutic target in alcohol users.

6. Evaluating glutathione peroxidase activity as a marker of cognitive impairment in coronary artery disease patients

Mehnaz Ahmed, MSc (1,2); Krista Lanctôt, PhD (1,2); Nathan Herrmann, MD (2); Ana Andreazza, PhD (2); Paul Oh, MD (3) 1. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada 2. Sunnybrook Research Institute, Toronto, Ontario Canada 3 University Health Network at Toronto Rehabilitation Institute, Toronto, Ontario Canada Introduction: Coronary artery disease (CAD) patients are at risk for vascular cognitive impairment (VCI), yet mechanisms remain elusive. Oxidative stress is involved in neurodegeneration. We hypothesized that glutathione peroxidase (GPx) activity, which protects from oxidative damage, would be higher in CAD patients with cognitive impairment reflecting a mild stage of VCI known as vascular cognitive impairment-no dementia (VCIND). Furthermore, it was hypothesized that baseline GPx activity and changes in GPx activity would be associated with changes in verbal memory performance over 6 months. Methods: CAD patients were recruited from the Toronto Rehabilitation Institute Cardiac Rehab (TRI-CR) program. Verbal memory performance, executive function performance and GPx activity were measured at baseline and 6-month timepoints. GPx activity was measured using an enzyme specific assay. Baseline GPx activity was compared in those with and without cognitive impairment, defined as performing at least 1 standard deviation (SD) below the population norm, using an ANCOVA. Baseline GPx activity and changes in GPx over 6-months were associated with changes in verbal memory over the same time frame using linear mixed model analyses. Results: In 120 CAD patients (aged 64±6 years, 84% male, mean MMSE: 28.7±1.3), GPx activity was significantly elevated in those with cognitive impairment (n=36) compared to those without (n=84) cognitive impairment (F1,119=3.996, p=0.048). While a 1 nmol/min/mL increase in GPx activity was associated with a decrease in verbal memory (b=-0.02, df=184.65, p=0.004) and executive function z-scores (b=-0.02, df=185.58, p=0.027) over 6 months, baseline GPx activity did not predict change in verbal memory. Conclusion: This research suggests that alterations in GPx activity may be associated with cognition in CAD patients, providing novel data suggesting the potential role of GPx as a mechanistically relevant biomarker for cognitive performance in patients at risk for VCI.

7. The association between suicidal ideation and perceived stress: a functional neuroimaging study

Katie L. Vandeloo (1,2), Patricia Burhunduli (1), Adel Farah (1,3), Pierre Blier (1,3) & Jennifer L. Phillips (1,2,3). 1) Mood Disorders Research Unit, the Royal’s Institute of Mental Health Research, Ottawa, ON, Canada 2) Neuroscience, Carleton University, Ottawa, ON, Canada 3) Psychiatry, University of Ottawa, Ottawa, ON, Canada Introduction: The significance of the progression from suicidal ideation (SI) to suicide attempts (SA) has been highlighted in individuals with treatment-resistant depression (TRD), in which the need for more objective biomarkers of the likelihood of a suicide attempt have been emphasized.


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Consequently, this study aims to identify functional imaging correlates of TRD and SI severity, in which alterations in fronto-limbic regions are expected. Methods: The present study included 25 individuals with TRD (n=14M, n=11F; mean age 42.08 ±12.7), in which the association between varying severities of SI and alterations in resting-state functional networks was investigated. The association between various clinical constructs and imaging data was also explored, including that of perceived stress and depression severity, as well as both self-report and clinician-rated measures of SI. Results: Analysis of clinical data revealed a significant correlation between clinician and self-rated measures of SI (p<0.001), SI and depression severity (p=0.005), as well as perceived stress and SI (p=0.034). Functional magnetic resonance imaging (fMRI) data was preprocessed and analyzed using the CONN Functional Connectivity SPM Toolbox (2017), with a focus on the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and amygdala. Preliminary results suggest reduced connectivity between the left OFC and the ACC in relation to greater SI severity (p=0.008; uncorrected), as well as reduced connectivity between the ACC and the left amygdala in relation to higher perceived stress (p=0.013; uncorrected). Conclusion: These preliminary, uncorrected results suggest that inter-region connectivity between the OFC, ACC and amygdala may be associated with SI and perceived stress. Further analysis with a larger sample size is hypothesized to obtain a more robust effect with a corrected analysis.

8. The effect of high-fat diet and exercise on neuroanatomy in a mouse model of Alzheimer’s disease

Chloe Anastassiadis1, BASc, Mila Urosevic1, Daniel Gallino1, MSc, Gulebru Ayranci1, PhD, Gabriel A. Devenyi1,2, PhD, Jurgen Germann1, PhD, & M. Mallar Chakravarty1,2,3, PhD 1Cerebral Imaging Center, Douglas Mental Health University Institute, Verdun, Quebec, Canada; 2Department of Psychiatry, McGill University, Montreal, Quebec, Canada; 3Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada Introduction: High-fat diet (HFD) is a risk factor for Alzheimer’s disease (AD), yet 1) its impact on neuroanatomy (the phenotype most proximate to cognitive deficits), and 2) its potential for rescue are not well-defined. Here we characterize both in a mouse model of AD, and we expect HFD to induce neuroanatomical deviations from normal aging that correlate with poorer memory function but can be rescued with exercise. Methods: To study the interaction of intervention with initial AD-like (amyloid beta aud tau) neuropathology, triple-transgenic (3Tg-AD) and wild-type mice were used. At 2 months they were assigned to either a HFD (60% kcal from fat) or a control diet (10% kcal from fat) (n=31); at 4 months mice on HFD either remained on that treatment (n=31), or were assigned to one of three rescues: exercise (n=34), return to a low-fat diet (n=33), or both (n=27). Structural magnetic resonance imaging (MRI) was acquired at 2, 4, and 6 months. The Morris water maze and novel object recognition tests were used to assess memory. Results: Linear mixed effect models were used to analyze MRI data and it was found that HFD led to a decrease in hippocampal volume, which was fully rescued by exercise but not by a return to a low-fat diet (FDR 5%). This was reflected by poorer cognitive performance of HFD mice compared to control and exercise-based rescue groups (p<0.05). Finally, 3Tg-AD mice had a decrease in volume in the hippocampal regions compared to wild-types (FDR 5%), but preliminary results suggest they also have less potential for intervention-induced plasticity. Conclusion: We have described subtle HFD-induced neuroanatomical changes that are well-correlated with cognitive function, even in rescued animals. However, the 3Tg-AD mice seem to be less responsive to those interventions, suggesting limited potential for plasticity at high levels of neuropathology.

9. Endothelial function affects cognition through angiogenesis in coronary artery disease patients


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Cameron Isaacs-Trepanier1,3, BSc; Nathan Herrmann2,3, MD FRCPC; Mahwesh Saleem3, PhD; Jane Mitchell1, PhD; Kim Sugamori1, PhD; Paul Oh4, MD; Krista Lanctot1,2,3, PhD 1. Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada 2. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada 3. Neuropsychopharmacology, Sunnybrook Research Institute, Toronto, Ontario, Canada 4. Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario, Canada Introduction: Vascular endothelial dysfunction is a hallmark of coronary artery disease (CAD) and is associated with an increased risk of vascular cognitive impairment (VCI). Mechanisms linking vascular health and cognitive decline remain unclear. Evidence suggests that poorer vascular health may lead to brain hypoperfusion by impairing angiogenesis, resulting in cognitive decline. This study aimed to assess a marker of angiogenesis (endostatin) as a mediator of the effects of endothelial function (EF) on cognition. We hypothesize that higher levels of endostatin representing impaired angiogenesis, will mediate the effects of endothelial dysfunction on cognition in patients with CAD, an at-risk population. Methods: Patients with CAD were recruited upon entry into a cardiac rehabilitation program. EF was measured by the reactive hyperemia index (RHI) using peripheral arterial tonometry. Endostatin, an anti-angiogenic marker, was measured in plasma using ELISA. Cognition was assessed using the Montreal Cognitive Assessment (MoCA). To examine the effects of RHI and endostatin on MoCA scores, a mediation analysis utilizing the PROCESS macro for SPSS was performed and the mediation product of coefficients (a x b) was assessed. An inferential bootstrapping procedure with 10,000 permutations was used to compute 95% confidence intervals (CI), and the result was significant if the bias-corrected bootstrap CI did not cross 0. The model controlled for total years of education and VO2max. Results: In CAD patients (mean age±SD = 64±7, 86% male, mean years of education±SD = 16±3, n=51), higher levels of endostatin mediated a significant indirect effect of RHI on poorer MoCA scores (a x b =0.58, 95% bootstrap CI [0.044–1.734] points). Conclusions: These findings suggest that peripheral endostatin may be an important marker of VCI in those with endothelial dysfunction. Since exercise can modulate EF and induce angiogenesis, exercise may be an important intervention to preserve cognition in CAD patients with elevated endostatin.

10. The timing of adolescence: chemicals and cues that control the transition to adulthood

Daniel Hoops; Kyne, Robert; Paul, Matthew; Flores, Cecilia Introduction: During adolescence, dopamine axons grow from the nucleus accumbens to the prefrontal cortex. This is critically important to the proper development and function of the prefrontal cortex in adulthood. The guidance cue Netrin-1, and its receptors, coordinate the growth of these axons. Methods: In mice we experimentally modify Netrin-1 levels along the dopamine axon route to determine whether we can control dopamine axon growth. Furthermore, we examine changes in Netrin-1 receptor expression on dopamine axons during adolescence, including after exposure to drugs of abuse. We use Siberian hamsters to test whether these changes are a fundamental characteristic of adolescent development. These hamsters time adolescent development to avoid winter. We look at whether the coordinated expression of Netrin-1, DCC, and UNC5c are age-dependent, or tuned to the timing of adolescence, independent of age.


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Results: Modifying Netrin-1 expression along the axon route results in dopamine axons being misdirected, and demonstrates that Netrin-1 signals to dopamine axons where to grow. Before adolescence, dopamine axons express high levels of the receptor DCC, which signals attraction to Netrin-1. However, during adolescence dopamine axons begin to express the receptor UNC5c, which binds DCC in the presence of Netrin-1 and inverses the signal to repulsion. We theorize that it is the appearance of UNC5c that determines when dopamine axons start growing to the prefrontal cortex. We found that the expression of Netrin-1 receptors during adolescence can be regulated by drugs of abuse, in turn altering cortical development and cognitive processing in adulthood. We also show that dopamine axon innervation to the prefrontal cortex in hamsters is timed to adolescence, irrespective of age. Conclusion: We show that the Netrin-1 signalling pathway is critical for understanding the neural changes underpinning adolescence. This pathway is also a promising site for targeted interventions in cases of psychiatric illness.

11. The serotonin transporter and ß-amyloid accumulation within the cell: different effects of selective serotonin reuptake inhibitors and tricyclic antidepressants

Jennifer N.K. Nyarko, PhD(1); Kaeli J. Knudsen, MSc(1); Ryan M. Heistad(1); Carlos E. Carvalho, PhD(2) and Darrell D. Mousseau, PhD(1). (1) Department of Psychiatry, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada. (2) Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada Rationale: Antidepressant drug usage can increase risk for Alzheimer disease (AD), with a greater risk associated with selective serotonin reuptake inhibitors (SSRIs) versus the original tricyclic antidepressants (TCAs). Both classes of drugs block the serotonin transporter (SERT), thereby implicating SERT in ß-amyloid (Aß) transport across cell membranes. Any interference in this transport mechanism would result in accumulation of Aß, an early event of AD. Methods: We obtained a transgenic strain of Caenorhabditis elegans (C. elegans) overexpressing a human AD-related Aß peptide (Aß1-42) under control of the muscle promoter. Accumulation of Aß1-42 in the muscle causes paralysis, quantifiable as a decrease in ‘thrashing’ behaviour. We also crossed these worms onto a truncated MOD-5 (C. elegans analog of SERT) background as well as a tryptophan hydroxylase (tph-1)-null background (to determine the influence, if any, of serotonin (5-HT)). Intracellular accumulation of Aß in these worms, and in immortalized mammalian cell cultures overexpressing an AD-related APP variant, was monitored across screens including SSRIs and TCAs. Results: An intracellular accumulation of Aß was observed in worms treated with SSRIs, but not TCAs. A similar phenotype was observed in worms expressing the truncated MOD-5 (with no drug treatment), but not in worms with a deletion of tph-1 (thus, the ‘paralysis’ phenotype was likely due to an effect mediated by SERT/MOD-5, rather than a change in 5-HT availability). Similar patterns were observed in our mammalian cell model. Conclusion: Pharmacological and genetic methods provided strong evidence that SERT can transport Aß out of the cell. This has potential implications for risk of AD in vulnerable clinical populations, with SSRIs having a greater effect than TCAs on SERT-mediated transport of Aß.

12. Orbitofrontal cortex is required for the retrieval of cue value in an aversive sensory preconditioning paradigm

Gostolupce D. Author, MA1 Graduate Student, Department of Psychology, CSBN, Concordia University, Montreal, Quebec, Canada Lay B. PhD, Department of Psychology, CSBN, Concordia University, Montreal, Quebec, Canada Iordanova, M. PhD, Department of Psychology, CSBN, Concordia University, Montreal, Quebec, Canada The orbitofrontal Cortex (OFC) is critical for encoding and retrieving information about cue value and does so in a flexible manner. One way the OFC does this is by making inferences about cue


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value as exemplified in sensory preconditioning. In sensory preconditioning a neutral cue becomes imbued with value via its association with anther initially neutral cue that has subsequently been trained to predict a valuable outcome. Much of the research studying the function of the OFC has focused solely on learning in the appetitive setting. Yet, cues can acquire not only positive but also negative value via their association with aversive events. Here we sought to examine the involvement of OFC in learning to infer aversive (fear) information using a sensory preconditioning procedure where a predictor for an aversive event supports learning . In our sensory preconditioning design, two originally neutral cues (e.g. tone-light) are paired through repeated presentations. Subsequently, one of those neutral cues is revalued through direct pairings with an aversive outcome. Interestingly, the cue that was never paired with the aversive outcome is also able to elicit a fear response via its association with the now revalued cue. Our data show that inactivation of lateral OFC (lOFC) during test, disrupts this process of inference evident by the attenuated fear response (freezing) to the sensory preconditioned cue. Therefore, our data provide evidence that the OFC is important for behavioural flexibility in an aversive setting. Keywords: orbitofrontal cortex, sensory preconditioning, aversive learning, stimulus-stimulus associations.

13. In-depth analysis of CYP2D6, a gene highly relevant for neuropsychopharmacology Beatriz Carvalho Henriques, BSc1; Yabing Wang, MD PhD1; Bahareh Behroozi Asl, BSc MSc1; Vasyl Yavorskyy1; Michael Carr1; Joshua Hague1; Xiuying Hu, MD MSc1; Chad Bousman2; Katherine J Aitchison1 Author affiliations: 1Departments of Psychiatry and Medical Genetics, University of Alberta, Edmonton, Alberta, Canada 2Departments of Medical Genetics, Psychiatry, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada Introduction: For the majority of medications used to treat mental health conditions, clinical guidelines [1] state that pharmacogenomics either could or should be used to tailor prescribing practice [2]. Fourteen of these drugs are antidepressants, six are antipsychotics, one (atomoxetine) is used for attention deficit hyperactivity disorder, and the remaining two are mood stabilizers. For the majority of these drugs, CYP2D6 and CYP2C19 are the actionable genes implicated, with HLA-A and HLA-B being implicated for the remaining drug-gene pairs. Despite this, genotyping for variants in these genes is not yet routinely clinically available. Part of the reason for this is the complexity of the CYP2D6 locus. Methods: Individuals from a large sample of individuals treated with antidepressants (Genome-based therapeutic drugs for depression, or GENDEP) for whom array data for CYP2D6 are inconsistent with copy number analyses are undergoing further analysis by methods including long-polymerase chain reaction (PCR) and sequencing. Results: In-depth CYP2D6 comparative analyses are providing valuable platform-platform data and identifying samples of unusual genotype, for potential reference samples. Conclusion: We are making progress towards development of robust and feasible assays for CYP2D6 with reference samples. It is our hope that this resource will lead to greater consistency between pharmacogenomics assays and interpretation thereof. References: 1. https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/ 2. Bousman, C., Maruf, A. A. & Muller, D. J. Curr Opin Psychiatry, doi:10.1097/YCO.0000000000000465 (2018).

14. The effect of hunger on the augmentation of heroin seeking in chronically food restricted rats

Vanessa Moman & Émilie Fortin, Alexandra Chisholm, Uri Shalev Dept. of Psychology and Centre for Studies in Behavioural Neurobiology (CSBN), Concordia University, Montreal, QC


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Our laboratory has previously demonstrated a robust increase in heroin seeking following a period of forced abstinence in chronically food-restricted rats as compared to sated rats. It is unclear whether this effect is due to the chronic nature of the restriction, or an acute state of hunger. Attempts at refeeding rats 2 or 24 hours prior to the drug-seeking test abolished the effect. It was hypothesized that a hunger state would not affect food restriction-induced augmentation of heroin seeking in abstinent rats. Male Long Evans rats were trained to self-administer heroin for 10 days (0.1 mg/kg/infusion; i.v.). They then entered an abstinence period for 16 days, where they were either food restricted (90% of baseline body weight) or received unlimited access to food (Sated). Restricted rats were fed at 8:00 am (FDRam) or at 1:30 pm (FDRpm). On last day of withdrawal, a 3-hour drug-seeking test was conducted at 9:30 am specifically to ensure the FDRam group would be in a sated state during the test, while the FDRpm group would be in a state of hunger. The FDRpm rats showed a statistically significant increase in heroin-seeking compared to the Sated rats (p = 0.2). FDRam rats did not show a statistically significant difference in heroin-seeking compared to the Sated rats. However, they did demonstrate an augmentation with a large Cohen's D effect size (d = 0.77). FDRam and FDRpm rats did not show statistically significant differences in their heroin-seeking, with a moderate effect size (d = 0.57). As expected, FDRpm rats demonstrated an augmented heroin seeking during the test compared to sated rats. Despite not reaching statistical significance, FDRam rats also showed an augmentation of heroin seeking, suggesting that hunger might have additional effects on the augmentation of heroin seeking induced by chronic food restriction in abstinent rats.

15. Effects of cholinergic receptor muscarinic 1 (CHRM1) and CYP1A2 gene variants on plasma ratio of clozapine/N-desmethylclozapine and working memory performance in schizophrenia

Farhana Islam, MSc1,2, Benoit H. Mulsant, MD3,4,5, Bruce G. Pollock, MD PhD3.4,5, Gary Remington, MD Phd3,4, James L. Kennedy, MD1,3,4, Daniel J. Müller, MD PhD1,2,3,4, Tarek K. Rajji, MD3,4,5 1 Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, Toronto, ON, Canada 2Department of Pharmacology, University of Toronto, Toronto, ON, Canada 3 Department of Psychiatry, University of Toronto, Toronto, ON, Canada 4 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada 5 Adult Neurodevelopment and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada Objective: Clozapine (CLZ) has variable impact on working memory (WM) in schizophrenia possibly due to opposing effects of CLZ and its metabolite, N-desmethylclozapine (NDMC) at the muscarinic M1 receptor (M1R). CLZ/NDMC ratio is a better predictor of WM performance than CLZ or NDMC levels alone. We assessed the contributions of genetic variations in CHRM1 and CYP1A2 on the relationship between CLZ/NDMC and WM. Methods: We assessed WM with the MATRICS Consensus Cognitive Battery and measured plasma CLZ and NDMC concentrations in 28 patients with schizophrenia on CLZ monotherapy. We evaluated two functionally significant SNPs, rs1942499 and rs2075748, in CHRM1, with rs2075748 T- and rs1942499 A-alleles associated with lower transcriptional activity than rs2075748 C- and rs1942499 G-alleles, respectively; we also studied CYP1A2 *1F, with *1F/*1F conferring high inducibility to smoking. Results: For rs2075748, CLZ/NDMC was correlated with WM in the CC (n = 18, rp = -0.59, p=0.04) and not the CT/TT (n = 10) group. No such correlation was observed in any rs1942499 group (n (AA) = 12, n (AG/GG) = 16). For CYP1A2, there was interaction between CYP1A2 genotype and smoking such that *1F/*1F smokers (n = 4) had significantly lower CLZ and NDMC levels than *1F/*1F non-smokers (n = 5) or (*1/*1 or *1/*1F) smokers (n = 7) and non-smokers (n = 11). Also, CLZ/NDMC was correlated with WM in the *1/*1 or *1/*1F group (rp = -0.49, p=0.04) but not the *1F/*1F group.


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Conclusions: For CHRM1 rs2075748, the CC genotype -associated with higher transcription for M1R- is also associated with a relationship between CLZ/NDMC and WM, supporting a cholinergic mechanism underlying this relationship. However, this was not supported by rs1942499 findings. These relationships and their interactions with CYP450 genetics need to be further studied in larger samples.

16. Abnormal fear generalization in schizophrenia Lauri Tuominen, MD PhD1,2,3, Stephanie N. DeCross, BA2, Emily A. Boeke, BA2,6, Roger B.H. Tootell, PhD3,4,5, Oliver Freudenreich, MD2,3, Ann K. Shinn, MD3,7, Daphne J. Holt, MD PhD2,3,4 1. University of Ottawa’s Institute of Mental Health Research, Ottawa, Ontario, Canada 2. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA 3. Harvard Medical School, Boston, Massachusetts,, USA 4. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA 5. Department of Radiology, Harvard Medical School, Boston, MA, USA 6. Department of Psychology, New York University, New York, NY, USA 7. McLean Hospital, Belmont, MA, USA Introduction: Generalization from previous experiences allows us to evaluate the affective value of novel events. A breakdown of this fundamental ability may lead to incorrect attributions of affective value that could give rise to psychotic symptoms. To examine this hypothesis, we tested whether the generalization of conditioned fear responses is abnormal in schizophrenia, using functional magnetic resonance imaging (fMRI). Methods: 37 schizophrenia and 32 healthy subjects, matched for age, and sex, underwent an fMRI scan while participating in a Pavlovian fear conditioning and generalization paradigm. During the conditioning phase, one face was used as a conditioned stimulus and paired with an electrical shock (the CS+), whereas a different face was used as a neutral stimulus that was never paired with a shock (the CS-). In the generalization phase, five stimuli that gradually morphed from the CS+ to the CS- were selected based on each individual’s ability to discriminate the two faces. Afterwards, subjects were asked to rate how likely each stimulus was to shock them (explicit ratings). Results: Patients with schizophrenia and controls were able to acquire conditioned fear. However, patients with schizophrenia exhibited impaired fear generalization associated with abnormal brain activity most prominently in the salience and default mode networks. More specifically, schizophrenia patients showed lower explicit ratings and lower activity in the salience network. In addition, schizophrenia patients showed impaired deactivation of the default mode network during fear generalization. Conclusions: Schizophrenia patients show impaired generalization of fear memories. This impairment in fear generalization is associated with abnormal functioning of the salience and default mode networks. These findings suggest that psychosis may arise in part from a deficit in the immediate retrieval of associative memory traces – a basic process that can be quantified as impaired fear generalization. The study was supported by the grant R01MH095904

17. Association between COMT methylation and response to treatment in children with ADHD

Weam Fageera1,2, Boris Chaumette1,3, Natalie Grizenko1,3, Sarojini M. Sengupta1,3, and Ridha Joober1,2,3

1Douglas Mental Health University Institute, Montreal, Quebec, Canada; 2Department of Human Genetics, McGill University, Montreal, Quebec, Canada; 3Department of Psychiatry, McGill University, Montreal, Quebec, Canada Background: The study of the epigenetic basis for the individual variation in drug response, is an area that has gained much interest recently. Indeed, epigenetic variations may provide another level of explanation for interindividual variations in drug response that cannot be accounted for on


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the basis of genetic polymorphism. This study aims to examine the association between DNA methylation of COMT gene and response to methylphenidate (MPH) and placebo (PBO) in children with ADHD. It also examines how SNPs in the gene encoding COMT could influence the DNA methylation levels. Methods: 230 children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial and were included in a methylation study. Association between the DNA methylation of 11 CpG sites spanning the genomic region of the COMT gene and PBO/MPH responses were assessed using Spearman's correlation analysis. Univariate analysis was performed to examine potential associations between genotype and DNA methylation where each SNP was the independent factor and level of methylation of each CpG site was the dependent factor. Results: Associations were observed between specific genetic variants and methylation level of cg20709110 (P = 0.029). In particular, homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), and Val/Val (rs4680) showed significant association with higher methylation at cg20709110. In addition, cg20709110 showed a significant correlation with PBO response (r2= .15, P=0.045) and MPH response (r2=.134, P=.05),where a better response to treatment was associated with less methylation at cg20709110. Conclusions: To the best of our knowledge, these are the first results that provide evidence for the involvement of the epigenetic variation of COMT in modulating response to treatment in ADHD.

18. Sex differences in resistance to reinstatement following overexpectation compound training

Vanessa Fernandez, Mihaela Iordanova; PhD, Andreas Arvanitogiannis; PhD Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, Canada Animal behaviour is highly adaptive and subject to modification in the face of changing contingencies. Two examples that lead to a reduction in a previously established behavioural response are overexpectation and extinction. In overexpectation, two individually reinforced cues are presented together in compound in order to generate an (over)expectation of double reinforcement. This compound is followed by a single reinforcer thereby leading to a mismatch between the cue-dependent expectation and the delivered reward. This mismatch drives a reduction in the reward expectation, such that subsequent presentation of one of those cues results in a reduced behavioural response. In extinction, a previously reinforced cue is presented in the absence of reinforcement, resulting in a progressive decrease in responding. Not only do both paradigms lead to the same behavioural outcome, that is; a reduction of a previously established behaviour, but they are also subject to the same restoration phenomena. The reduced behavioural response is restored following a change in context (renewal) or following the passage of time (spontaneous recovery) following extinction as well as overexpectation. In addition to renewal and spontaneous recovery, extinction is also subject to reinstatement where exposure to the reinforcing outcome alone following extinction learning causes a return of the behavioural response upon presentation of the extinguished cue. It has not been investigated whether unsignaled outcome presentations are also effective at reinstating the behavioural response following overexpectation training. Here we investigated this by using an appetitive overexpectation design in male and female rats. After going through the overexpectation paradigm, it was demonstrated that female but not male rats were resistant to the reinstatement effect. These findings showcase the importance of investigating and documenting sex differences in basic behavioural paradigms.

19. GABA/glutamate ratios in the medial prefrontal cortex and the left dorsolateral prefrontal cortex of perimenopausal women

Jessica Luki, BSc (Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada), Christopher Hanstock, PhD (Department of Biomedical Engineering, University of Alberta,


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Edmonton, Alberta, Canada), Peter Seres (Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada), Surina Grover (Department of Biology, University of Alberta), Alynna Lirette, BSc (Department of Medicine, University of Alberta, Edmonton, Alberta, Canada), Tami Shandro, MD (Royal Alexandra Hospital, Edmonton, Alberta, Canada), Katherine Aitchison, PhD (Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada), and Jean-Michel Le Melledo, MD (Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada Introduction: An increased risk of depressive symptomatology is seen in women during events associated with fluctuations of female hormones. We will measure GABA and Glutamate (Glu) in perimenopausal women to see if they are affected by female hormones. Perimenopause, occurring prior to menopause, carries a greater risk for first onset and recurrence of an episode of major depression (MD). GABA and Glu are respectively responsible for inhibitory and excitatory transmission, and it has been suggested that their imbalance could play a role in the pathophysiology of depression. Previous studies demonstrated that Glu and GABA are dysregulated in other depressive disorders triggered by fluctuations of female hormones. GABA and Glu, antagonistic neurotransmitters, have not been measured simultaneously in depression research, making the interpretation of one neurotransmitter’s dysregulation difficult without information of the other. Methods: We used magnetic resonance spectroscopy (MRS) to simultaneously measure Glu and GABA. We compared the ratios of GABA/Glu in the medial prefrontal cortex (MPFC) to the left dorsolateral prefrontal cortex (LDLPFC) in healthy controls (HC), as activity of these two brain regions have been shown critical in mood symptomatology. Six perimenopausal women, screened for the absence of past/current mental illnesses, were scanned using a 3 Tesla Siemens Prisma MR scanner during the follicular phase of their menstrual cycle. An optimized PRESS localization sequence was used for acquisition of the glutamate signal, and a MEGA-PRESS sequence for the selective measurement of GABA. Results: There was a statistical trend suggesting that MPFC GABA/Glu ratios (0.906±0.235) were lower than LDLPFC GABA/Glu ratios (1.194±0.343, p= 0.067). Conclusion: Considering the statistical trend and our small sample size, recruitment of additional HCs and comparison with MD patients may lead to valuable information for the understanding of how female hormones affect GABA/Glu ratios in the MPFC and LDLPFC in the brain of perimenopausal women.

20. Children with ADHD homozygous for the NET (rs36021) risk allele have reduced cortical surface area in executive brain regions: Evidence for an overdominance model

Nellie H. Fotopoulos1,2, Sarojini M. Sengupta1,3, Gabriel A. Devenyi1,3, Sherif Karama1,3,5, M. Mallar Chakravarty1,3,6, Natalie Grizenko1,3, and Ridha Joober1,2,3,4

1 Douglas Mental Health University Institute, Montréal, Québec, Canada 2 Department of Human Genetics, McGill University, Montréal, Québec, Canada 3 Department of Psychiatry, McGill University, Montréal, Québec, Canada 4 Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada 5 Montréal Neurological Institute, Montréal, Québec, Canada 6 Department of Biological and Biomedical Engineering, McGill University, Montréal, Québec, Canada The norepinephrine transporter (NET) is implicated in ADHD pathophysiology and is responsible for the reuptake of NE and DA in the prefrontal cortex, a region robustly associated with ADHD. A previous study by our team found a significant association between a SNP within NET (rs36021) and ADHD diagnosis and cognitive measures. We used structural MRI to investigate rs36021


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genotype group effects on brain structure in a clinical sample of children with ADHD (n=74). Cortical brain structures were compared among three rs36021 genotype groups (AA=23, AT=28, TT=23). RMINC, CIVET-1.1.12 and MAGeT-Brain were used to perform linear modelling, acquire cortical thickness and surface area, and obtain subcortical volumes in 51 regions, respectively. Multiple-testing correction using FDR was performed. Significant brain regions were tested for associations with cognitive measures (CBCL). In comparison to the AT genotype group, mean cortical thickness was significantly smaller in the AA group (left hemisphere df=69, p=.0397; right df=69; p=.0317) and TT group (left df=69; p=.0388; right df=69; p=.0381). Total surface area was significantly reduced in the TT group (left df=69; p=.00393; right df=69; p=.00389). No global cortical differences were detected between AA and TT genotype groups. Vertex-wise comparison yielded reductions in surface area (left tmax=3.26; 15% FDR; right tmax=3.37; 10% FDR) between AT and TT genotype groups in the orbitofrontal, frontal and temporal regions. No effects between genotype groups and subcortical volumes were detected. CBCL externalizing (df=70; p=.007), aggression (df=70; p=.0329), oppositional defiant problems (df=69; p=.0258), conduct disorder (df=70; p=.0263) and rule-breaking (df=70; p=.0316) standardized scores were higher in children homozygous for the T-risk allele compared to heterozygous children (AT). This study remains in line with a previous report linking the T-risk allele with more severe ADHD symptomatology and behavioural measures, and provides additional evidence of an overdominance model for rs36021 genotype groups.

21. Association of polygenic risk score with quantitative measures of behaviour and response to treatment with methylphenidate in children with ADHD

Sarojini M. Sengupta PhD1,2, Calwing Liao3, Marie-Ève Fortier PhD1, Natalie Grizenko MD, FRCPC1,2, Ridha Joober MD, PhD 1,2,3,4 Author affiliations: 1. Douglas Mental Health University Institute 2. Department of Psychiatry, McGill University 3. Department of Human Genetics, McGill University 4. Integrated Program in Neuroscience, McGill University Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a complex and highly prevalent psychiatric disorder among school-aged children. It is well established that ADHD is a polygenic disorder where multiple susceptibility genes contribute to overall risk, each with a small effect. The medications used most commonly to treat ADHD symptoms are psychostimulants (primarily methylphenidate [MPH] derivatives). Significant variability in clinical response is observed, and it has been hypothesized that genetic factors may account for differences in treatment outcome. However, clinical and genetic predictors of treatment response have not yet been identified in spite of the myriad reports. Over the past 20 years, 870 children affected with ADHD have participated in a prospective double-blind placebo-controlled pharmaco-behavioural genetic study (with a fixed dose of methylphenidate, MPH), funded mainly by CIHR (PIs: RJ and NG). Methods: The DNA from each of the children who provided verbal assent (with signed consent from the parent), was genotyped using the Illumina® Global Screening Array at the Broad Institute, Harvard University (via collaboration between RJ and the Psychiatric Genetics Consortium). Polygenic risk scores (PRS) were calculated for each individual after LD-pruning and testing different significance thresholds. Correlation analysis was then conducted with quantitative measures of behaviour, cognition and treatment response. Results: Significant moderate correlation was observed between PRS and: (1) number of hyperactivity items, based on the evaluation by the clinician and the parental interview (DISC); (2) number of conduct disorder and oppositional defiant items on the DISC; (3) treatment response as evaluated by parents at home and teacher at school. Conclusion: These preliminary results suggest that polygenic risk score shows a significant association with quantitative measures of behaviour and treatment response. However further


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work is required to determine how these associations are moderated by exposure to specific pre/per-natal environmental factors.

22. Effects of combined psychological and metabolic stress on behavior and physiology

Brett Melanson,BSc Thomas Lapointe,BA Francesco Leri,PhD Department of Psychology, University of Guelph, Guelph, ON, Canada Chronic stress is highly implicated in the development of depression, possibly through elevation of inflammatory cytokines such as interleukin (IL)-6, IL-1ß, IL-17A and tumour necrosis factor (TNF)-a. The primary objective of the current project in laboratory rats was to explore the relationship between combined psychological and metabolic stressors, inflammatory cytokines, and depressive-like behavior to uncover markers of response to antidepressants. Two experiments have been performed in male Sprague-Dawley rats. In Experiment 1, rats were exposed to repeated sessions of inescapable swimming stress to explore behavioral indices of despair (forced swim test), as well as circulating levels of inflammatory cytokines. In Experiment 2, repeated swimming stress was combined with exposure to a metabolic stressor (0, 200 and 300 mg/kg 2-deoxy-D-glucose; 2DG) to explore impact on behavioral despair, anhedonia (saccharin preference), as well as circulating levels of corticosterone and inflammatory cytokines. Experiment 1 indicated that multiple sessions of swimming stress induced long-lasting behavioral despair (p < 0.001), but levels of inflammatory cytokines were not affected (p > 0.05). In Experiment 2, the addition of the metabolic stressor dose-dependently increased despair responses (p = 0.048), corticosterone (p = 0.001) and TNF-a (p = 0.020). Moreover, rats treated with 200 and 300mg/kg 2DG displayed a significant reduction in saccharin consumption (p < 0.001). In summary, the current results in laboratory rats suggest that inflammatory cytokines may play a role in depressive-like behaviors when exposure to uncontrollable stress is of considerable intensity and duration. Moreover, establishing a functional protocol for inducing a significant inflammatory response to multimodal stress allows further investigation into the effects of conventional and novel antidepressant medications.

23. Repeated sub-anesthetic administration of ketamine maintains an increase in dopamine and norepinephrine neuron activity

Iro, C. M., El Mansari, M., Blier P.; The Royal’s Institute of Mental Health Research Ottawa, ON and the University of Ottawa, Ottawa, ON Background: A single infusion of ketamine has rapid antidepressant effect, although the drawback is a lack of sustained effect. Our previous study showed a rapid enhancement (within 2 hours) in ventral tegmental area (VTA) dopamine (DA) neurons population and locus coeruleus (LC) norepinephrine (NE) firing and bursting activity following a single ketamine administration. The current study investigated whether these changes are present 24 hours after a single administration and if they are maintained with repeated administration. Methods: Ketamine (10mg/kg, i.p.) was administered to male Sprague Dawley rats once or repeatedly (3 times/week) for 2 weeks. After single and repeated administration of ketamine, electrophysiological recordings were done in the VTA and LC in anesthetized rats, 24 hrs, 3 or 7 days post-administration. Spike frequency, bursting, and for VTA neurons, spontaneously active neurons/trajectory were assessed. Results: In the VTA, the previously observed increase in number of DA neurons/tract was no longer present 24 hrs after ketamine was injected acutely, but persisted with repeated injections (N=5, p=0.02). Although there was no increase in DA neurons bursting 24 hrs after a single ketamine injection, this was enhanced following repeated administration. This bursting activity persisted after 3 days but dissipated after 7 days (N=5, p=0.03). In LC, there was an increase in


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spike frequency of NE neurons observed 24 hrs following repeated administration (N=5, p<0.001), but dissipated after 3 days (p<0.001). Conclusion: These results indicate that repeated but not acute administration of ketamine maintained the increase in population activity of DA neurons and firing activity of NE neurons.

24. Lithium use in older age bipolar disorder (OABD): special considerations Jocelyn Fotso Soh1, M.Sc., Sivan Klil-Drori1, MD., Soham Rej1,2, MD, M.Sc. 1Geri-PARTy Research group, Department of Psychiatry, Jewish General Hospital, Montreal, QC 2Dept. of Psychiatry, McGill University, Montreal, QC Introduction: Lithium is the gold standard treatment for bipolar disorder. It is effective in the management of manic, depressive, and maintenance phases of bipolar disorder treatment. Despite this, the implications of lithium use in the older population remain less understood. This critical narrative review aims to better understand the impact of lithium in older age bipolar disorder (OABD), including tolerability and efficacy, based on up to date evidence. Methods: Relevant studies of efficacy, effectiveness, and tolerability published any time prior to May 2018 were identified using the PubMed keyword search: “lithium older adult bipolar disorder” and references from recent international bipolar disorder guidelines. Results: One randomized controlled trial was identified, the GERI-BD (Acute Pharmacotherapy in Late-Life Mania) study. This study found lithium to be effective in late-life mania and hypomania. The remaining literature examining lithium in OABD was reviewed, comprising of a number of small open-label and retrospective studies, with special considerations highlighted. Conclusion: In summary, there is a small, yet increasing geriatric evidence base that lithium is effective in OABD. Although there can be adverse effects with lithium, it is generally well tolerated, and there are methods to minimize these risks. Further research would strengthen the evidence base for lithium therapy in OABD. In the meantime, lithium remains the gold-standard treatment for OABD.

25. Effects of adolescent ∆9-tetrahydrocannabinol exposure on adult rat brain structure Anthony C. Vernon (PhD, FHEA) [1], Sotiris G. Kakanos (MSc) [1], Eugene Kim (PhD) [2], Dulcie A. Vousden (PhD) [3], Jason P. Lerch (PhD) [3] and Sagnik Bhattacharyya (MD, PhD) [4]. [1] Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom [2] Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada [4] Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom Background: Clinical and pre-clinical studies suggest cannabis consumption during adolescence is associated with increased risk for psychiatric illness in later life. We therefore set out to identify the specific neuroanatomical circuits by which adolescent cannabis exposure may predispose the developing brain for later onset of psychopathology. To do so, we combined a validated rat model of adolescent exposure to ∆9-tetrahydrocannabinol (∆9-THC) with a hypothesis-free assessment of adult rat brain macrostructure using structural MRI (sMRI) and voxel-wise computational neuroanatomical analysis tools. Methods: Male Sprague-Dawley rats were exposed to escalating (2.5; 5; 10 mg/kg; i.p.; n=10) doses of ∆9-THC or drug vehicle during adolescence, defined as post-natal day 35-45. Animals were left undisturbed until adulthood (P80), sacrificed by anaesthetic overdose and perfusion-fixed prior to high resolution ex vivo 3D MRI. The MRI data were then analysed for group level differences using unbiased voxel-wise tensor-based morphometry and automated cortical thickness analysis, corrected for multiple comparisons using the family-wise error rate (FWE


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p<0.05). Results: ∆9-THC exposure in adolescence was confirmed by an increase in drug plasma levels on P44 (653±140 nM [30 minutes post-dosing at 10 mg/kg], equivalent to 205.3 ng/ml). After correction for multiple comparisons, there were however no statistically significant effects of adolescent ∆9-THC exposure on either adult rat brain volume or cortical thickness at P80. Nominally significant (p<0.01 uncorrected for multiple comparisons) volume and cortical thickness decreases were observed in the frontal cortex of ∆9-THC-exposed rats, with additional volume decreases in the striatum, ventral midbrain, thalamus and cerebellum (all p<0.01 uncorrected). Conclusion: Our data suggest that adolescent ∆9-THC exposure has subtle long-term effects on adult rat brain macrostructure. Nominally significant region-specific changes were however found in brain regions of relevance to psychiatric illness. Longitudinal in vivo MRI studies are now required to confirm these findings and their functional relevance.

26. Reduced dopamine release in Dcc haploinsufficient mice protects against the rewarding effects of stimulant drugs, but not morphine and alcohol

Dominique Nouel, PhD1*; Emmanuel Darcq, PhD 1,2*; Matthew Pokinko, MSc1; Luc Moquin, MSc1; Alain Gratton, PhD1,2; Brigitte Kieffer, PhD1,2 and Cecilia Flores, PhD1, 2. 1 Douglas Mental Health University Institute, Montréal, Québec, Canada 2 Department of Psychiatry, McGill University, Montréal, Québec, Canada *contributed equally to this work Background: The DCC/Netrin-1 guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens (NAcc) in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug. Whether the protective effects of Dcc haploinsufficiency are selective to stimulant drugs of abuse or instead extrapolate to opioids and alcohol remains to be established. Methods and Results: We used the conditioned place preference (CPP) paradigm to assess rewarding effects of cocaine (20 mg/kg), morphine (5 or 10 mg/kg) and alcohol (2g/kg) in adult male Dcc haploinsufficient mice and their wild-type counterparts. While wild-type mice exposed to cocaine showed robust CPP compared to saline-treated controls, cocaine-treated Dcc haploinsufficient mice did not develop CPP. In contrast, all mice exposed to morphine and alcohol developed CPP, regardless of phenotype. To begin assessing whether these drug-dependent effects result from drug-specific changes in dopamine release in the NAcc we used in vivo microdialysis. To our surprise, Dcc haploinsufficient mice show reduced dopamine release in response to morphine in comparison to wild-type mice. Conclusion: Our main findings are two-fold: (1) Dcc haploinsufficiency protects against rewarding effects of stimulants via reduced dopamine release in the NAcc, but not of morphine and alcohol. This is consistent with our recent study showing that humans with DCC haploinsufficiency have reduced incidence of cigarette smoking, but not of alcohol consumption, compared to their relative controls (Vosberg et al., 2018 J Neurosci); (2) there is a dissociation between the effects of morphine on reward and on NAcc dopamine release. This idea that dopamine receptor blockade or lesions of the mesolimbic dopamine do not decrease opioid reward was reviewed in (Badiani et al, 2011 Nature Reviews) and is consistent with our findings.

27. Validation of [11C]ABP688 as a promising PET tool to quantify glutamate release in vivo


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Hussein Bdair, BSc Pharm, MSc 1,2,3; Luc Moquin 2; Alexey Kostikov, PhD 1,3; Chawki Benkelfat, MD, CSPQ, DERBH 2; Alain Gratton, PhD 2; Marco Leyton, PhD 1 2 – 1 McGill University, McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal H3A 2B4, QC, Canada. 2 McGill University, Department of Psychiatry, Irving Ludmer Psychiatry Research and Training Building, Montreal H3A 1A1, QC, Canada. 3 McGill University, Department of Neurology and Neurosurgery, 3801 University St, Montreal H3A 2B4, QC, Canada Introduction: The excitatory neurotransmitter glutamate plays a critical role in drug-seeking behaviour, drug withdrawal and experience-dependent neuroplasticity. Nevertheless, studying glutamate release in humans is impeded by a lack of tools. ABP688 is a highly selective allosteric antagonist of metabotropic type 5 glutamate (mGlu5) receptors. Positron emission tomography (PET) studies with the 11C-radiolabelled ligand, [11C]ABP688, in humans and laboratory animals have reported alterations in tracer binding in response to glutamate-release enhancing or suppressing interventions. These observations raise the possibility that [11C]ABP688 might provide a non-invasive method to measure synaptic glutamate release. Objective: Investigate whether drug-induced changes in extracellular glutamate release are proportional to changes in [11C]ABP688 binding, using simultaneous microdialysis and microPET. Methods: Lewis strain rats (n=5) were implanted with a microdialysis cannula into unilateral nucleus accumbens (NAc). Following a one-week recovery period, they received two microPET/[11C]ABP688 scans on separate days accompanied by simultaneous in-vivo microdialysis with a dose of 0.5g/kg of either saline or 20% ethanol injected intraperitoneally. Results: The microdialysis data identified a significant ethanol-induced increase in NAc glutamate concentrations of 24.6±15.9% during the first 20 min (p=0.03). The greater the increase in extracellular glutamate, the greater the decrease in [11C]ABP688 binding (r=0.982, p=0.003). The ratio of mean percentage glutamate release to mean percentage tracer binding was 6:1, comparing very favourably to the 44:1 ratio seen for [11C]raclopride and amphetamine-induced dopamine responses. Conclusion: These results provide the first evidence that [11C]ABP688 provides an index of quantitative changes in extracellular glutamate release, opening the door to the non-invasive measure of glutamate release in living human brain.

28. Are adolescent suicidal behaviors related to differences in cortical thickness development?

Anthony Gifuni1, Plitman, Eric1,2, Chakravarty, Mallar1,2, Renaud, Johanne1,3, Jollant, F1,4 1McGill Group for Suicide Studies, Douglas Mental Health University Institute 2Computational Brain Anatomy Laboratory, Douglas Mental Health University Institute 3Manulife Centre for Breakthroughs in Teen Depression and Suicide Prevention 4Paris Descartes University & Sainte-Anne Hospital, Paris. Introduction: Suicidal behaviors represent a major source of adolescent mortality and morbidity. During adolescence, cortical grey matter undergoes significant maturational changes detectable at the macrostructural level. Structural anomalies emerging during adolescent brain development could favor suicidal vulnerability. Methods: Three groups of adolescents were recruited: patients with a depressive disorder and a history of suicide attempts (SA; N=33, mean age=16.2±1.01, females=79%), psychiatric controls with a depressive disorder and without a history of suicide attempt (PC; N =37, mean age 16.1±1.48, females=78%), and healthy controls (HC; N =30, mean age=15.2±1.44, females=73%). T1-weighted structural scans were acquired with 3T magnetic resonance imaging. Cortical thickness was measured in 68 regions bilaterally, after surfaces reconstruction with FreeSurfer 5.3. Linear regression modeling examined the effect of group, age, and their interaction while controlling for gender and IQ.


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Results: Significant differences in the interaction between age and cortical thickness were found in SA compared to PC and HC (F>4.0, p<0.05) in the right insula, left superior temporal and right inferior temporal cortex. Post-hoc analyses revealed that instead of declining with age, cortical thickness was correlated positively with age in SA only. Comparisons of regional cortical thickness at the level of the whole group (controlling for age) did not reveal any significant difference (FDR threshold= 0.05). Conclusion: This study suggests that deficient structural maturation in regions implicated in social cognition, visual perception and emotions may contribute to a heightened suicide risk during adolescence. Longitudinal studies and larger sample sizes are necessary to confirm the regional specificity of these findings.

29. Memories that linger: effect of acute and conditioned opiate withdrawal on memory consolidation

Nana Baidoo, Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada. Michael Wolter, Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada. Boyer Winters, PhD, Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada. Francesco Leri, PhD, Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada Introduction: Opiate withdrawal can be associated to a context through classical conditioning to produce conditioned withdrawal. To explore the role of conditioned withdrawal in memory processes, this research investigated whether conditioned withdrawal could impact memory consolidation. Two experiments in males Sprague-Dawley rats compared the effects of naltrexone-precipitated withdrawal and conditioned morphine withdrawal on consolidation of object recognition memory. Methods: In Experiment 1, 3 mg/kg naltrexone was administered immediately, or 6 hours, post-sample to morphine-naïve and morphine-dependent animals (osmotic mini-pumps; 10 mg/kg/day). The post-training effects of naltrexone were re-tested 7 days following removal of the pumps. In Experiment 2, morphine-naïve and morphine dependent rats were confined for 2 hours in a distinctive chamber (CS+) following naltrexone injections (1 or 3 mg/kg) and in another chamber (CS-) following vehicle injections. This was repeated for 10 days: 5 naltrexone/CS+ pairings and 5 vehicle/CS- parings. The effects of immediate or delayed (6 hrs) post-sample exposure to the CS+ and CS- were tested during dependence, and 7 days following removal of pumps. Results: Experiment 1 found that 3 mg/kg naltrexone enhanced object recognition memory when administered immediately, but not 6 hours, post-training in morphine dependent and post-dependent, but not morphine-naïve, rats. During conditioning in the CS+, Experiment 2 found that naltrexone suppressed locomotor activity, caused rapid body weight loss, and increased frequency of wet dog shakes in morphine-dependent rats only. When confined in the CS+ without naltrexone injections, rats displayed suppressed locomotion, weight loss and wet-dog shakes. More importantly, exposure to CS+ immediately, but not 6 hours, post-training enhanced object recognition memory during dependence and post-dependence. Conclusions: These experiments indicate that both acute precipitated and conditioned withdrawal have significant and persistent faciliatory effects on memory consolidation. This suggests that conditioned effects on memory processes can play a significant role in addictive behaviours.

30. Context-induced renewal of avoidance in the shock-probe defensive burying task


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Isabelle Richard 1; Alexa Brown, BA 1; Melissa Martins 1; Nadia Chaudhri, PhD 1. 1. Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, QC, Canada Introduction: Avoidance of potential threats or environmental stressors is a primary symptom of many psychiatric diseases. Context can be a crucial determinant of the presence or absence of threats. Here, we examined the capacity of context to renew extinguished active or passive coping behaviours in the shock-probe defensive burying task. Methods: We tested context-induced renewal using ABA, ABC and AAB designs, where consecutive letters refer to the context in which training, extinction and test occur. Male, Long-Evans rats (220-240 g on arrival; Charles River) were handled and habituated to Contexts A, B and C. Next they were exposed to an electrified shock-probe (3 mA on contact) in Context A across 3, 15 minute sessions. Rats then received 5 extinction sessions and 2 tests where the probe was unarmed. Tests were counterbalanced within-subjects, and occurred either in the renewal or extinction contexts. Video-scored dependent variables included probe burying, probe avoidance, probe contacts in frequency, duration, and latency to first contact. Results: Rats did not consistently bury the probe during training, but robustly avoided the side of the chamber containing the armed shock probe, suggesting a propensity for passive coping. Probe avoidance extinguished across sessions when the probe was unarmed, with no differences across extinction in Context A versus Context B. A return to the training context produced marked ABA renewal of avoidance, number of probe contacts and duration of probe contact. ABC renewal was not observed based on group averages, although this effect was evident in a subset of rats. Finally, a test in Context B following training and extinction in Context A produced a surprising, significant reduction in avoidance. Conclusions: These findings highlight a role for context in the development and expression of conditioned avoidance, providing the new evidence that context can renew passive avoidant behaviour.

31. Social defeat stress in adolescence dysregulates Dcc/Netrin-1 system 1,2 Andrea Harée Pantoja Urbán, MSc; 2 Dominique Nouel, PhD; 2 Michel Giroux; 2,3 Cecilia Flores, PhD. 1Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada. 2Douglas Mental Health University Institute, Montréal, Québec, Canada. 3Department of Psychiatry, McGill University, Montréal, Québec, Canada Stress in adolescence increases susceptibility to psychopathology. This is partly attributed to the protracted maturation of prefrontal cortex (PFC) dopamine circuitry. Specifically, dopamine axons are still growing toward the PFC throughout adolescence, remaining susceptible to environmental events. This process is controlled by the guidance receptor gene Dcc, which in turn determines adult PFC connectivity and cognitive function in adulthood. Whether stress in adolescence alters Dcc expression and consequently dopamine development remains unknown. Here we adapted the adult 10-day chronic social defeat stress model to adolescent mice to examine whether social stress in adolescence (i) induces social avoidance and (ii) alters Dcc in the ventral tegmental area (VTA). We used an accelerated social defeat stress (ASD) paradigm whereby adolescent C57/BL6 male mice were introduced (10 min) twice a day to a different CD-1 mice for a total of 4 days. CD-1 mice were introduced to an adult mouse for 30 sec prior to the adolescent mouse. A standard social interaction test was used to measure social avoidance and segregate mice into resilient and susceptible groups. Dcc mRNA VTA levels were quantified using qPCR. ASD was also performed in female mice. The majority (~60%) of mice exposed to ASD in adolescence, regardless of sex, showed resiliency as they did not develop social avoidance. ASD did not induce anxiety-like behavior in either male or females, but male resilient mice showed increased risk-taking-like behavior compared to control and susceptible groups. ASD reduced VTA Dcc mRNA regardless of vulnerable phenotype. The large number of susceptible mice exposed to ASD in


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adolescence is intriguing and suggests that this age may be protective. Similar studies in adult mice will assess this question. Reduced VTA Dcc expression in adolescence disrupts PFC dopamine development. Thus, the Dcc downregulation by stress suggests possible alterations in mesocortical dopamine development.

32. A pre-clinical model of operant binge drinking in rats Zoë Ward, Mandy R. LeCocq, BA, Sophie Sun, Nadia Chaudhri, PhD Psychology, Center for Studies in Behavioural Neurobiology, Concordia University, Montréal, QC, H4B 1R6, Canada Introduction: Binge drinking is a hazardous way to consume alcohol. It produces rapid escalations in blood alcohol concentrations that can cause neuroadaptations leading to alcohol use disorder. We aimed to develop a preclinical model of binge drinking in rats, based on a procedure developed by Jeanblanc et al. (2018, Addict. Biol). Specifically, we tested if shortening the length of self-administration sessions promoted binge-like levels of alcohol intake. Methods: Rats (male; Long Evans; Envigo) received intermittent access to alcohol (20% v/v ethanol) in the home cage to familiarize them with its taste and pharmacological effects. Rats then underwent operant alcohol self-administration training, during which pressing an active lever (fixed-ratio 1, n = 8; fixed-ratio 3, n = 16) resulted in one alcohol reinforcer (0.1 mL/reinforcer) delivered into a fluid port for oral intake. The initial 1 h session length was incrementally shortened to 30 min, then 15 min over eight weeks. Results: On average, rats on both schedules of reinforcement obtained a similar number of alcohol reinforcers during the 1 h and 15 min sessions. A subset of these rats (Fixed ratio 1: n = 3; Fixed ratio 3: n = 2) also met the criteria for binge drinking, by self-administering an ethanol dose of = 0.8 g/kg in the 15 min sessions. Further, initial home-cage alcohol intake was positively correlated with later operant alcohol intake. Conclusions: The findings from this study suggest that shortening the duration of access to alcohol self-administration promotes binge-like drinking in a subset of rats. This model can be used to study aspects of human binge drinking, like voluntary intake and underlying motivational processes. It also allows for the neural underpinnings and risk factors of binge drinking to be explored and targeted for therapeutic intervention.

33. mGlu5 receptor availability in emerging adults at risk for addictions: effects of vulnerability traits and cannabis use

Sylvia M.L. Cox1, Maria Tippler1, Natalia Jaworska2, Natalie Castellanos-Ryan3, Kelly Smart1, France Durand1, Dominique Allard1, Chawki Benkelfat1, Alain Dagher1, Frank Vitaro3, Sophie Parent3, Michel Boivin4, Robert O. Pihl1, Sylvana Côté3, Richard E. Tremblay3, Jean R. Séguin3, Marco Leyton.1 1 McGill University, Montreal, QC, Canada; 2 The Royal Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; 2 Université de Montréal, Montréal, QC, Canada; 4 Université Laval, Québec, QC, Canada. Background: Type 5 metabotropic glutamate (mGlu5) receptors are implicated in drug-induced neuroplasticity. In humans, their availability is altered in those with alcohol, tobacco, and cocaine use disorders. Since mGlu5 reductions could reflect either drug use or pre-existing traits, we used positron emission tomography (PET) to measure mGlu5 availability in emerging adults at elevated risk for addictions. Methods: Fifty-nine participants (18-20 y.o.) were recruited from a longitudinal cohort that has been followed since birth. Based on diverse externalizing behaviors that predict future substance use problems, half of the participants were at low risk, half were at high risk. Cannabis use histories varied markedly, and participants were divided into three groups: zero, low and high use. Participants were scanned on a high-resolution research tomograph PET with [11C]ABP688 and 3T magnetic resonance imaging for anatomical co-registration. Results: Compared to low risk volunteers, those at elevated risk for substance use disorders had


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lower [11C]ABP688 binding potential (BP) values in cortico-limbic regions including the striatum, amygdala, insula, and orbitofrontal cortex (OFC). A 2x3 rmANCOVA revealed a significant cannabis use by risk group interaction in the striatum and the OFC. In these regions, [11C]ABP688 BP values were significantly lower in the high risk individuals with high cannabis use histories, as compared to other groups. When the high risk, high cannabis use individuals (n=9) were compared to all other participants (n=50), [11C]ABP688 BP values were significantly lower in the striatum, OFC, and insula. These effects were evident when controlling for the use of other substances. Conclusion: Together, the present results provide the first evidence of a neurobiological mechanism by which adolescent cannabis use could increase the risk of psychiatric disorders in vulnerable populations.

34. Direct serotonin system stimulation via optogenetics as treatment for post-stroke depression in a mouse model

Min Zhang,MSc; Faranak Vahid-Ansari,PhD; and Paul R. Albert,PhD Affiliation: OHRI Neuroscience, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada Introduction: Selective serotonin reuptake inhibitors (SSRIs), which enhance serotonin (5-HT), are the first-line treatment for depression, but they require three weeks before antidepressant effect, and are only 50% effective in clinic. We hypothesize that direct stimulation of the 5-HT system can overcome these issues. Using optogenetics, we explored the antidepressant effect of direct stimulation of the 5-HT system at the dorsal raphe nucleus (DRN) in a mouse model of post-stroke depression. Methods: A unilateral ischemic lesion in the left medial prefrontal cortex was used to induce a persistent anxiety and depression phenotype. Transgenic mice expressing the opsin channelrhodopsin-2 (ChR2) in Pet1-positive cells were used to target 5-HT neurons for constant light-induced activation. An optic fiber was implanted above the DRN at a 20° angle to deliver blue light at 1- or 3-mW (Low/High) intensity at the fiber tip. One week after the stroke PSD mice underwent three anxiety and two depression tests with two rest days between each test. Each test had sequential 3-5 minute light OFF-ON-OFF epochs to compare acute differences in behaviour. The tests used included the elevated-plus maze, open field and novelty-suppressed feeding for anxiety-like behaviour, and the tail-suspension and forced swim tests for behavioral despair. Results: 1-mW stimulation resulted in an anxiolytic effect post-stimulation while showing antidepressant effects only in mice carrying 2 copies of the ChR2 gene. 3-mW stimulation produced an acute anxiogenic effect and a significant antidepressant effect that persisted after the end of stimulation period in behaviour tests. Conclusions: Our results suggest that direct activation of the 5-HT system can produce a ChR2-dose dependent acute antidepressant effect and a light dose-dependent increase in anxiety-like behaviour. These results indicate that stimulation intensity of 5-HT neurons may produce stronger or opposite actions on behaviour. Supported by CPSR and HSF.


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POSTER PRESENTER POSTER POSTER SESSION NUMBER Ahmed, Mehnaz 2 6 Albeely, Abdalla 1 20 Anastassiadis, Chloe 2 8 Baidoo, Nana 2 29 Bdair, Hussein 2 27 Blostein, Nadia 1 23 Boachie, Nadia 1 35 Borduas, Eric 2 4 Brown, Alexa 1 10 Burhunduli, Patricia 2 1 Carvalho Henriques, Beatriz 2 13 Chen, Jinghan Jenny 1 18 Cox, Sylvia M.L. 2 33 De Zavalia, Nuria 1 2 Delorme, Tara 1 24 Dudek, Katarzyna Anna 2 3 Fageera, Weam 2 17 Farina, Antonio 1 32 Fernandez, Vanessa 2 18 Fotopoulos, Nellie H. 1; 2 4; 20 Fotso Soh, Jocelyn 2 24 Gaudette, Erin 1 16 Gifuni, Anthony 2 28 Gostolupce, Dilara 2 12 Hamati, Rami 1 34 Hernandez, Giovanni 1 9 Hoops, Daniel 2 10 Iro, Chidiebere Michael 2 23 Isaacs-Trepanier, Cameron 2 9 Islam, Farhana 2 15 Joseph, Antoneta T. 1 31 Khau, Michelle 1 1 Khoo, Shaun Y.-S. 1 14 Larosa, Amanda 1 6 Lay, Belinda P.P. 1 28 LeCocq, Mandy R. 1 11 Lemonde, Ann-Catherine 1 27 Luki, Jessica 2 19 Maes, Etienne JP. 1 21 Majeur, Simon 1 8 Melanson, Brett 2 22 Mio, Megan 1 19 Moman, Vanessa 2 14 Moon, Eunsoo 1 22 Nath, Moushumi 1 3 Ndiaye, Ndeye Aissatou 1 33 Nouel, Dominique 2 26 POSTER PRESENTER POSTER POSTER SESSION NUMBER


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Nyarko, Jennifer N.K. 2 11 Pantoja Urbán, Andrea Harée 2 31 Richard, Isabelle 2 30 Schottner, Konrad 1 30 Sengupta, Sarojini M. 1; 2 5; 21 Servonnet, Alice 1 25 Teskey, Grace 2 2 Thiyagarajah, Mathura T. 1 17 Truong, Jennifer 2 5 Tullo, Stephanie 1 29 Tuominen, Lauri 2 16 Vahid-Ansari, Faranak 1 13 Valyear, Milan D. 1 12 Vandeloo, Katie L. 2 7 Vernon, Anthony C. 2 25 Villaruel, Franz R. 1 7 Ward, Zoë 2 32 Waye, Shannon 1 26 Zhang, Min 2 34 Zou, Yi 1 15

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